J. Med. Chem.

Correction to Malaria-Infected Mice Are Completely Cured by One 6 mg/kg Oral Dose of a New Monomeric Trioxane Sulfide Combined with Mefloquine.

Publication Date: 2012 Feb 2 PMID: 22299638
Authors: Slack, R. D. - Mott, B. T. - Woodard, L. E. - Tripathi, A. - Sullivan, D. - Nenortas, E. - Girdwood, S. C. - Shapiro, T. A. - Posner, G. H.
Journal: J Med Chem

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Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A beta-Lactamase.

Publication Date: 2012 Feb 1 PMID: 22296601
Authors: Nichols, D. A. - Jaishankar, P. - Larson, W. - Smith, E. - Liu, G. - Beyrouthy, R. - Bonnet, R. - Renslo, A. R. - Chen, Y.
Journal: J Med Chem

The emergence of CTX-M Class-A extended-spectrum beta-lactamases poses a serious health threat to the public. We have applied structure-based design to improve the potency of a novel non-covalent tetrazole-containing CTX-M inhibitor (Ki = 21 microM) more than 200-fold via structural modifications targeting two binding hotspots - a hydrophobic shelf formed by Pro167 and a polar site anchored by Asp240. Functional groups contacting each binding hotspot independently in initial designs were later combined to produce analogs with sub-micromolar potencies, including 6-trifluoromethyl-3H-benzoimidazole-4-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide, which had a Ki value of 89 nM and reduced the MIC of cefotaxime by 64-fold in CTX-M-9 expressing Escherichia coli. The in vitro potency gains were accompanied by improvements in ligand efficiency (from 0.30 to 0.39) and LipE (from 1.37 to 3.86). These new analogs represent the first nM-affinity non-covalent inhibitors of a Class A beta-lactamase. Their complex crystal structures provide valuable information about ligand binding for future inhibitor design.

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Identification of Binding Specificity-Determining Features in Protein Families.

Publication Date: 2012 Jan 30 PMID: 22289061
Authors: Anderson, P. C. - De Sapio, V. - Turner, K. M. - Elmer, S. P. - Roe, D. C. - Schoeniger, J. S.
Journal: J Med Chem

A new approach is presented for identifying features of ligand-protein binding interfaces that predict binding selectivity. Established approaches such as clustering based on similarities of experimentally determined binding affinity profiles can define binding-specificity classes of proteins and ligands, but cannot alone reveal the structural and chemical features of the interactions that determine the specificity of molecular recognition. We analyzed a large set of human kinases and kinase inhibitors using both clustering based on experimentally determined inhibition constants to define specificity classes of kinases and inhibitors, and virtual ligand docking to extract structural and chemical features of the ligand-protein binding interfaces. We then used statistical methods to identify sets of features characteristic of each class. We employed machine learning to determine which combinations of the identified class-specific features were predictive of class membership and to predict binding specificities and affinities of compounds from outside the training data set. Laboratory experiments found that the predictions were accurate in 70% of cases. These results show that pharmacophore-like features of three-dimensional binding interfaces, which act as "selectivity filters," can be pinpointed automatically using the presented computational pipeline. This method is not restricted to kinases, requires no prior hypotheses about specific interactions, and can be applied to any protein families for which sets of structures and ligand binding data are available.

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Gold-Containing Indoles as Anti-Cancer Agents that Potentiate the Cytotoxic Effects of Ionizing Radiation.

Publication Date: 2012 Jan 30 PMID: 22289037
Authors: Craig, S. - Gao, L. - Lee, I. - Gray, T. G. - Berdis, A. J.
Journal: J Med Chem

This report describes the design and application of several distinct gold-containing indoles as anti-cancer agents. When used individually, all gold-bearing compounds display cytostatic effects against leukemia and adherent cancer cell lines. However, two gold-bearing indoles show unique behavior by increasing the cytotoxic effects of clinically relevant levels of ionizing radiation. Quantifying the amount of DNA damage demonstrates that each gold-indole enhances apoptosis by inhibiting DNA repair. Both Au(I)-indoles were tested for inhibitory effects against various cellular targets including thioredoxin reductase, a known target of several gold compounds, and various ATP-dependent kinases. While neither compound significantly inhibits the activity of thioreoxin reductase, both showed inhibitory effects against several kinases associated with cancer initiation and progression. The inhibition of these kinases provides a possible mechanism for the ability of these Au(I)-indoles potentiate the cytotoxic effects of ionizing radiation. Clinical applications of combining Au(I)-indoles with ionizing radiation are discussed as a new strategy to achieve chemosensitization of cancer cells.

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Substituted 3-(5-Imidazo[2,1-b]thiazolylmethylene)-2-indolinones and Analogues: Synthesis, Cytotoxic Activity and Study of the Mechanism of Action.

Publication Date: 2012 Jan 30 PMID: 22283430
Authors: Andreani, A. - Granaiola, M. - Locatelli, A. - Morigi, R. - Rambaldi, M. - Varoli, L. - Calonghi, N. - Cappadone, C. - Farruggia, G. - Stefanelli, C. - Masotti, L. - Nguyen, T. L. - Hamel, E. - Shoemaker, R. H.
Journal: J Med Chem

The synthesis of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and analogues is reported. Their cytotoxic activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. The action of selected compounds was examined for potential inhibition of tubulin assembly in comparison with the potent colchicine site agent combretastatin A-4. The most potent compounds also strongly and selectively inhibited the phosphorylation of the oncoprotein kinase Akt in cancer cells. The effect of the most interesting compounds was examined on the growth of HT-29 colon cancer cells. These compounds caused the cells to arrest in the G2/M phase of the cell cycle, as would be expected for inhibitors of tubulin assembly.

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Continuous Flow Synthesis. A Pharma Perspective.

Publication Date: 2012 Jan 27 PMID: 22283413
Authors: Malet Sanz, L. - Susanne, F.
Journal: J Med Chem

Continuous flow chemistry as a technique and the latest developments in the field are being reviewed from a Pharma point of view.

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Design, Synthesis and Biological Evaluation of 1-[(2-benzyloxyl/alkoxyl) methyl]-5-halo-6-aryluracils as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Improved Drug Resistance Profile.

Publication Date: 2012 Jan 27 PMID: 22283377
Authors: Wang, X. - Zhang, J. - Huang, Y. - Wang, R. - Zhang, L. - Qiao, K. - Li, L. - Liu, C. - Ouyang, Y. - Xu, W. - Zhang, Z. - Zhang, L. - Shao, Y. - Jiang, S. - Ma, L. - Liu, J.
Journal: J Med Chem

Since the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug-resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using Nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. The compound 7b, that had the highest selectivity index (SI = 38,215), is more potent than Nevirapine and 18. These results suggest that introduction of halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, m-substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with improved antiviral efficacy and drug-resistance profile.

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Identification and Structure-Activity Relationships of a Novel Series of Estrogen Receptor Ligands Based on 7-Thiabicyclo[2.2.1]hept-2-ene-7-oxide.

Publication Date: 2012 Jan 26 PMID: 22283328
Authors: Wang, P. - Mian, J. - Nwachukwu, J. C. - Cavett, V. - Carlson, K. E. - Guo, P. - Zhu, M. - Dong, C. - Katzenellenbogen, J. A. - Nettles, K. W. - Zhou, H. B.
Journal: J Med Chem

To develop ligands for the estrogen receptor (ER) that have novel structures and activities, we have explored compounds in which the central hydrophobic core has, overall, a more three-dimensional topology than is typically found in both steroidal and non-steroidal estrogen ligands. Extension to the third dimension is designed to exploit the unfilled space above and below the ligand in the ER ligand-binding pocket and thereby enhance receptor binding or subtype selectivity. In this study, we build upon our previous investigations on the three-dimensional core structure ligand, 7-oxabicyclo[2.2.1]heptene or heptadiene, by replacing the oxygen bridge with a sulfoxide. These new 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide compounds were conveniently prepared by a Diels-Alder reaction of various 3,4-diarylthiophenes with a variety of dienophiles in the presence of an oxidant. Structure-activity relationships (SARs) for these derivatives were then investigated. Several of these new compounds demonstrated high binding affinities with excellent selectivity for the ERalpha subtype. Unlike oxabicyclic compounds, which showed little ER agonist activity, many thiabicyclic compounds demonstrated potent, ERalpha-selective agonist activity in transcriptional assays. Molecular models suggest that the observed gain in activity is due to key differences in stereoselectivity that enable the thiabicyclic compounds to stabilize the active conformation of ERalpha. Further, our data suggests that the disposition of methyl groups in the appended phenyl substituents in the C-5 and C-6 positions of the bicyclic core unit contribute to the binding affinity and subtype selectivity exhibited by these novel ER ligands.

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Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides.

Publication Date: 2012 Jan 26 PMID: 22280453
Authors: Carmi, C. - Galvani, E. - Vacondio, F. - Rivara, S. - Lodola, A. - Russo, S. - Aiello, S. - Bordi, F. - Costantino, G. - Cavazzoni, A. - Alfieri, R. R. - Ardizzoni, A. - Petronini, P. G. - Mor, M.
Journal: J Med Chem

Irreversible EGFR inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or aspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved as efficient as their acrylamide analogs in inhibiting EGFR-TK autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

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'True' antiandrogens - selective non ligand-binding pocket disruptors of androgen receptor-coactivator interactions: Novel Tools for Prostate Cancer.

Publication Date: 2012 Jan 26 PMID: 22280402
Authors: Caboni, L. - Kinsella, G. K. - Blanco, F. - Fayne, D. - Jagoe, W. N. - Carr, M. - Williams, D. C. - Meegan, M. J. - Lloyd, D. G.
Journal: J Med Chem

Prostate cancer therapy (PCa) typically involves administration of 'classical' antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand binding pocket (LBP) in the ligand binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening. Compounds demonstrate full ('true') antagonism in AR with low micromolar potency, selectivity over Estrogen Receptors alpha and beta and Glucocorticoid Receptor, with partial antagonism in the Progesterone Receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of 'classical' antiandrogen induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.

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Defining the Mechanism of Action and Enzymatic Selectivity of Psammaplin A Against its Epigenetic Targets.

Publication Date: 2012 Jan 26 PMID: 22280363
Authors: Baud, M. - Leiser, T. - Haus, P. - Samlal, S. - Wong, A. C. - Wood, R. - Petrucci, V. - Gunaratnam, M. - Hughes, S. - Buluwela, L. - Turlais, F. - Neidle, S. - Meyer-Almes, F. J. - White, A. J. - Fuchter, M. J.
Journal: J Med Chem

Psammaplin A is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: Histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that psammaplin A functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC50 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7 and W138 cells, with the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation, but little effect on tubulin acetylation. Finally, we have found no evidence for psammaplin A functioning as a DNMT inhibitor.

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Binding Affinity Prediction for Ligands and Receptors Forming Tautomers and Ionization Species: Inhibition of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2).

Publication Date: 2012 Jan 26 PMID: 22280316
Authors: Natesan, S. - Subramaniam, R. - Bergeron, C. - Balaz, S.
Journal: J Med Chem

Treatment of ionization and tautomerism of ligands and receptors is one of the unresolved issues in structure-based prediction of binding affinities. Our solution utilizes the thermodynamic master equation, expressing the experimentally observed association constant as the sum of products, each valid for a specific ligand-receptor species pair, consisting of the association microconstant and the fractions of the involved ligand and receptor species. The microconstants are characterized by structure-based simulations, which are run for individual species pairs. Here we incorporated the multispecies approach into the QM/MM Linear Response method, and used it for structural correlation of published inhibition data on mitogen activated protein kinase (MAPK)-activated protein kinase (MK2) by 66 benzothiophene and pyrrolopyridine analogs, forming up to five tautomers and seven ionization species under experimental conditions. Extensive cross-validation showed that the resulting models were stable and predictive. Inclusion of all tautomers and ionization ligand species was essential: the explained variance increased to 90 %, from 66 % for the single-species model.

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A Click Chemistry Approach to Pleuromutilin Derivatives, Part 2: Conjugates with Acyclic Nucleosides and their Ribosomal Binding and Antibacterial Activity.

Publication Date: 2012 Jan 26 PMID: 22280300
Authors: Nielsen, P. - Dreier, I. - Kumar, S. - Sondergaard, H. - Rasmussen, M. L. - Hansen, L. H. - Kongsted, J. - Vester, B.
Journal: J Med Chem

Pleuromutilin is an antibiotic that binds to bacterial ribosomes and thereby inhibit protein synthesis. A new series of semisynthetic pleuromutilin derivatives were synthesised using a click chemistry strategy. Pleuromutilin was conjugated by different linkers to a nucleobase, nucleoside or a phenyl group, as a side-chain extension at the C22 position of pleuromutilin. The linkers were designed on the basis of the best linker from our first series of pleuromutilin derivatives following either conformational restriction or an isosteric methylene to oxygen exchange. The binding of the new compounds to the Escherichia coli ribosome was investigated by molecular modeling and chemical footprinting of nucleotide U2506, and it was found that all the derivatives bind to the specific site and most of them better than pleuromutilin itself. The effect of the side-chain extension was also explored by chemical footprinting of nucleotide U2585 and the results showed that all the compounds interact with this position at a varying degree. Derivatives with a conformational restriction of the linker generally had a higher affinity than the derivatives with an isosteric exchange of one of the carbons in the linker with a hydrophilic oxygen. A growth inhibition assay with three different bacterial strains showed significant activity of several of the novel compounds.

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Optimization of Hydroxybenzothiazoles as Novel Potent and Selective Inhibitors of 17beta -Hydroxysteroid Dehydrogenase 1 (17beta-HSD1).

Publication Date: 2012 Jan 26 PMID: 22277094
Authors: Spadaro, A. - Frotscher, M. - Hartmann, R. W.
Journal: J Med Chem

17beta-HSD1 is a novel target for the treatment of estrogen-dependent diseases as it catalyzes intracellular estradiol formation. Starting from two recently described compounds, highly active and selective inhibitors were developed. The benzoyl compound 6 and the benzamide 17 are the most selective compounds toward 17beta-HSD2 described so far. They also showed a promising profile regarding activity in T47D cells, ERalpha and beta affinity, inhibition of hepatic CYP enzymes, metabolic stability and inhibition of marmoset 17beta-HSD1 and 17betaHSD2.

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Synthesis and Evaluation of the Cytotoxicities of Tetraindoles: Observation that the 5-Hydroxy Tetraindole (SK228) Induces G2 Arrest and Apoptosis in Human Breast Cancer Cells.

Publication Date: 2012 Jan 25 PMID: 22277074
Authors: Li, W. S. - Wang, C. H. - Ko, S. - Chang, T. T. - Jen, Y. C. - Yao, C. F. - More, S. V. - Jao, S. C.
Journal: J Med Chem

Current chemical and biological interest in indole-3-carbinol (I3C) and its metabolites has resulted in the discovery of new biologically active indoles. As part of a program aimed at the development of indole analogs, tetraindoles 1-15 were prepared and their antiproliferative effects on human breast cancer cells were evaluated. The results show that the 5-hydroxy-tetraindole 8 (SK228) has optimum antiproliferative activity against breast adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity involves G2-phase arrest of the cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2. Further observations suggest that 5-hydroxy-tetraindole 8 induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. Given the fact that I3C and its metabolites have been shown to improve therapeutic efficacy and to have a broad range of antitumor activities in human cancer cells, the current findings have important pharmacological relevance as they open a promising route to the development of a potential chemotherapeutic application of tetraindoles as agents for the treatment of breast cancer.

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Highly potent and selective fluorescent antagonists of the human adenosine A3 receptor based on the 1, 2, 4-triazolo[4,3-a]quinoxalin-1-one scaffold.

Publication Date: 2012 Jan 25 PMID: 22277057
Authors: Vernall, A. - Stoddart, L. - Briddon, S. - Hill, S. - Kellam, B.
Journal: J Med Chem

The adenosine-A3 receptor (A3AR) is a G protein-coupled receptor that shows promise as a therapeutic target for cancer, glaucoma, and various autoimmune inflammatory disorders, and as such there is a need for molecular probes to study this receptor. Here we report a series of fluorescent ligands containing different linkers and fluorophores based around a 1,2,4-triazolo[4,3-a]quinoxalin-1-one antagonist. One of these conjugates (19) displayed high affinity for the A3AR (pKD = 9.36 +/- 0.12) and is >650-fold selective over other adenosine receptor subtypes. Confocal microscopy revealed clear, displaceable membrane labeling of CHO-A3 cells with 19, with no detectable labeling of CHO-A1 cells under identical conditions. This fluorescent ligand was also able to specifically label the A3AR in HEK293T cells containing a mixed adenosine receptor population. The subtype specificity, along with its excellent imaging properties, make 19 an ideal tool for studying A3AR distribution and organization, particularly in the presence of other adenosine receptor subtypes.

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Synthesis, Anticancer Activities, and Cellular Uptake Studies of Lipophilic Derivatives of Doxorubicin Succinate.

Publication Date: 2012 Jan 25 PMID: 22276998
Authors: Singh, B. - Mandal, D. - Parang, K.
Journal: J Med Chem

A number of lipophilic 14-substituted derivatives of doxorubicin were synthesized through conjugation of doxorubicin-14-hemisucinate with different fatty amines or tetradecanol to enhance the lipophilicity, cellular uptake, and cellular retention for sustained anticancer activity. The conjugates inhibited the cell proliferation of human leukemia (CCRF-CEM, 69-76%), colon adenocarcinoma (HT-29, 60-77%), and breast adenocarcinoma (MDA-MB-361, 66-71%) cells at a concentration of 1 muM after 96-120 h incubation. N-Tetradecylamido derivative of doxorubicin 14-succinate (10) exhibited consistently comparable anti-proliferative activity to doxorubicin in a time-dependent manner (IC50 = 77 nM in CCRF-CEM cells). Flow cytometry analysis showed a 3-fold more cellular uptake of 10 than doxorubicin in SK-OV-3 cells. Confocal microscopy revealed that the conjugate was distributed in cytoplasmic and perinuclear areas during the first 1 h incubation and slowly relocalized in the nucleus after 24 h. The cellular hydrolysis study showed 98% of compound 10 was hydrolyzed intracellularly within 48 h and released doxorubicin.

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A New Strategy for the Development of Highly Potent and Selective Plasmin Inhibitors.

Publication Date: 2012 Jan 25 PMID: 22276953
Authors: Saupe, S. M. - Steinmetzer, T.
Journal: J Med Chem

A new structure-based strategy for the design of potent and selective plasmin inhibitors was developed. These compounds could be prepared by cyclizations between the P3 and P2 amino acid residues of substrate-analogue inhibitors using metathesis or a copper-catalyzed azide alkyne cycloaddition in combination with standard peptide couplings. The most potent bis-triazole derivative 10 inhibits plasmin and plasma kallikrein with K(i) of 0.77 and 2.4 nM, respectively, whereas it has poor activity against the related trypsin-like serine proteases thrombin, factor Xa, or activated protein C. Modeling experiments revealed that inhibitor 10 adopts a compact and rigid structure that fits well into the relatively open active site of plasmin and plasma kallikrein, while it is rejected from sterically demanding residues present in loops of the other enzymes. These results from modeling confirm the selectivity profile found for inhibitor 10 in enzyme kinetic studies. Such compounds might be useful lead structures for the development of new antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce bleeding complications.

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Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivo.

Publication Date: 2012 Jan 26 PMID: 22276570
Authors: Carta, F. - Aggarwal, M. - Maresca, A. - Scozzafava, A. - McKenna, R. - Masini, E. - Supuran, C. T.
Journal: J Med Chem

A series of dithiocarbamates was prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of 4 human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. X-ray crystal structure of hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compounds, which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed effective intraocular pressure lowering activity in an animal model of glucoma.

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Fragment-based and Structure-guided Discovery and Optimization of Rho Kinase Inhibitors.

Publication Date: 2012 Jan 24 PMID: 22272748
Authors: Li, R. - Martin, M. P. - Liu, Y. - Wang, B. - Patel, R. A. - Zhu, J. - Sun, N. - Pireddu, R. - Lawrence, N. J. - Li, J. - Haura, E. B. - Sung, S. S. - Guida, W. C. - Schonbrunn, E. - Sebti, S. M.
Journal: J Med Chem

Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK 1 (IC50 = 650 nM) and ROCK 2 (IC50 = 670 nM) whereas compound 24 was more selective for ROCK2 (IC50 = 100 nM) over ROCK 1 (IC50 = 1690 nM). Crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.

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Acylthiourea, Acylurea and Acylguanidine Derivatives with potent Hedgehog inhibiting Activity.

Publication Date: 2012 Jan 23 PMID: 22268551
Authors: Solinas, A. - Faure, H. - Roudaut, H. - Traiffort, E. - Schoenfelder, A. - Mann, A. - Manetti, F. - Taddei, M. - Ruat, M.
Journal: J Med Chem

The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. Based on the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72 and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.

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OXAPHOSPHINANES: NEW THERAPEUTIC PERSPECTIVES FOR GLIOBLASTOMA.

Publication Date: 2012 Jan 23 PMID: 22268526
Authors: Clarion, L. - Jacquard, C. I. - Odile, S. C. - Loiseau, S. - Filippini, D. - Hirlemann, M. H. - Volle, J. N. - Virieux, D. - Lecouvey, M. - Pirat, J. L. - Bakalara, N.
Journal: J Med Chem

This paper reports the design and synthesis of a new family of compounds, the phostines, belonging to the [1,2]oxaphosphinane family. 26 compounds have been screened for their antiproliferative activity against a large panel of NCI cancer cell lines. Because of its high synthesis yield and low EC50 value (500 nM against the C6 rat glioma cell line) compound 3.1a was selected for further study. Moreover the specific biological effect of 3.1a on the glioblastoma phylogenetic cluster from the NCI is dependent on its stereochemistry. Within that cluster, 3.1a has a higher antiproliferative activity than temozolomide and is more potent than paclitaxel for the SF295 and SNB75 cell lines. In constrast with paclitaxel and vincristine, 3.1a is devoid of astrocyte toxicity. The original activity spectrum of 3.1a on the NCI cancer cell line panel allows the development of this family for use in association with existing drugs, opening new therapeutic perspectives.

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Strategies for The Design of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors: Lessons from The Development of Seven Representative Paradigms.

Publication Date: 2012 Jan 23 PMID: 22268494
Authors: Li, D. - Zhan, P. - De Clercq, E. - Liu, X.
Journal: J Med Chem

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) in clinical use, such as nevirapine, delavirdine, efavirenz, etravirine and rilpivirine, a new drug approved by FDA recently, are key components of standard highly active antiretroviral therapy (HAART) against HIV infection. Despite great improvements in NNRTI efficacy and resistance profiles, there is still an urgent need for novel drugs possessing high potency with overcoming drug resistance, less toxicity with good patient adherence, and better pharmacokinetic properties. Currently, the 3-dimensional structure of HIV reverse transcriptase (RT) has been elucidated, but the inherent flexibility and mutability of the NNRTI binding pocket (NNIBP) still limit the structure-based NNRTI design . With the continued efforts in the development of computational tools and increased structural information on reverse transcriptase, coordinated multidisciplinary efforts involving medicinal chemistry (bioisosterism, molecular hybridization, scaffold hopping and fragment-based drug discovery), structural biology (crystallography), and computational chemistry (molecular modeling), have proven to be powerful strategies to handle the flexibility and mutability of the NNIBP for identifying new generation of NNRTIs. In this review, we took a look at the convoluted development routes of seven representative drugs and candidates (i.e., etravirine, rilpivirine, IDX-899, RDEA806, UK-453061, MK-4965 and BILR 355) that entered into clinical trials in the past 5 years, to highlight various drug design strategies implemented with a multidisciplinary approach so as to offer useful references to medicinal chemists for the discovery and development of novel NNRTIs. Furthermore, an elaborate pharmacophore model with same pharmacophoric features, and ubiquitous motifs of the halogenphenyl and nitrile groups that served as "privileged scaffolds" in fragment-based NNRTIs discovery strategy, are also specifically addressed.

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New pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): chemical synthesis and pharmacological evaluation.

Publication Date: 2012 Jan 23 PMID: 22268448
Authors: Liegeois, J. F. - Deville, M. - Dilly, S. - Lamy, C. - Mangin, F. - Resimont, M. - Tarazi, F. I.
Journal: J Med Chem

A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized in order to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D2L, D4, serotonin 5-HT1A, 5-HT2A and adrenergic 2A receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine, JL13 (1) and other diarylazepine derivatives. In terms of multi-receptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar and more flexible side chains are not favourable in this context. 2 and 5 were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to 1 and other second-generation antipsychotic drugs, repeated treatment with 2 significantly increased D1 and D4 receptors in nucleus accumbens and caudate putamen, and D2 receptors in medial prefrontal cortex and hippocampus while 5 significantly increased D2 and D4 receptors in nucleus accumbens. In addition, 2 increased 5-HT1A and decreased 5-HT2A receptors in cerebral cortex. In contrast, 5 did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of 2 as a novel second-generation antipsychotic agent.

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N-PHOSPHONOCARBONYLPYRROLIDINE DERIVATIVES OF GUANINE: A NEW CLASS OF BI-SUBSTRATE INHIBITORS OF HUMAN PURINE NUCLEOSIDE PHOSPHORYLASE.

Publication Date: 2012 Jan 23 PMID: 22264015
Authors: Rejman, D. - Panova, N. - Klener, P. - Maswabi, B. - Pohl, R. - Rosenberg, I.
Journal: J Med Chem

A complete series of pyrrolidine nucleotides, (3R)- and (3S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acids and (3S,4R)-, (3R,4S)-, (3S,4S)-, and (3R,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acids, were synthesised and evaluated as potential inhibitors of purine nucleoside phosphorylase (PNP) isolated from peripheral blood mononuclear cells (PBMCs) and cell lines of myeloid and lymphoid origin. Two compounds, 2a (S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acid and 6a (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid were recognised as nanomolar competitive inhibitors of PNP isolated from cell lines with Ki values within the ranges of 16-100 nM and 10-24 nM, respectively. The low MESGKi and PiKi values of both compounds for PNP isolated from PBMCs suggest that these compounds could be bi-substrate inhibitors that occupy both the phosphate and nucleoside binding sites of the enzyme.

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Dynamic Combinatorial Mass Spectrometry Leads to Inhibitors of a 2-Oxoglutarate Dependent Nucleic Acid Demethylase.

Publication Date: 2012 Jan 23 PMID: 22263962
Authors: Woon, E. C. - Demetriades, M. - Bagg, E. A. - Aik, W. - Krylova, S. M. - Ma, J. H. - Chan, M. - Walport, L. J. - Wegman, D. W. - Dack, K. N. - McDonough, M. A. - Krylov, S. N. - Schofield, C. J.
Journal: J Med Chem

2-Oxoglutarate dependent nucleic acid demethylases are of biological interest because of their roles in nucleic acid repair and modification. Although some of these enzymes are linked to physiology, their regulatory roles are unclear. Hence there is a desire to develop selective inhibitors for them; we report studies on AlkB which reveal it as being amenable to selective inhibition by small molecules. Dynamic combinatorial chemistry linked to mass spectrometric analyses (DCMS) led to the identification of lead compounds, one of which was analyzed by crystallography. Subsequent structure guided studies led to the identification of inhibitors of improved potency, some of which were shown to be selective over two other 2OG oxygenases. The work further validates the use of the DCMS method and will help to enable the development of inhibitors of nucleic acid modifying 2OG oxygenases both for use as functional probes and, in the longer term, for potential therapeutic use.

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Rapid Development of Piperidine Carboxamides as Potent and Selective Anaplastic Lymphoma Kinase Inhibitors.

Publication Date: 2012 Jan 20 PMID: 22263917
Authors: Bryan, M. C. - Whittington, D. A. - Doherty, E. M. - Falsey, J. R. - Cheng, A. C. - Emkey, R. - Brake, R. L. - Lewis, R. T.
Journal: J Med Chem

Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC50 = 0.174 microM) during high throughput screening, with selectivity over the highly related kinase insulin-like growth factor-1 (IGF1R). The X-ray co-crystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.

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Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2'-Des-methyl-sulindac Sulfide Scaffold.

Publication Date: 2012 Jan 20 PMID: 22263894
Authors: Liedtke, A. J. - Crews, B. A. - Daniel, C. M. - Blobaum, A. L. - Kingsley, P. J. - Ghebreselasie, K. - Marnett, L. J.
Journal: J Med Chem

Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogs for inhibition of COX-1. Several potent and selective inhibitors were discovered and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR3). The compounds inhibited tumor cell proliferation but only at concentrations > 100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogs may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

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Identification and Preliminary Characterization of a Potent, Safe and Orally Efficacious Inhibitor of Acyl-CoA:Diacylglycerol Acyltransferase 1.

Publication Date: 2012 Jan 20 PMID: 22263872
Authors: Souers, A. J.
Journal: J Med Chem

A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective and orally bioavailable compound 14. Oral administration at doses >/= 0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.

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Development of Potent and Selective Inhibitors of Aldo-Keto Reductase 1C3 (type 5 17beta-hydroxysteroid dehydrogenase) Based on N- Phenyl-Aminobenzoates and Their Structure Activity Relationships.

Publication Date: 2012 Jan 20 PMID: 22263837
Authors: Adeniji, A. O. - Twenter, B. M. - Byrns, M. C. - Jin, Y. - Chen, M. - Winkler, J. D. - Penning, T. M.
Journal: J Med Chem

Aldo-keto reductase 1C3 (AKR1C3; type 5 17beta-hydroxysteroid dehydrogenase) is overexpressed in castrate resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5alpha-dihydrotestosterone. Selective AKR1C3 inhibitors are required since compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5alpha-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular are potent but non-selective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid as lead compound, five classes of structural analogs were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads towards new therapeutics for CRPC.

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[1,2,4]Triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: Antagonists of the Wnt Pathway That Inhibit Tankyrases 1 and 2 via Novel Adenosine Pocket Binding.

Publication Date: 2012 Feb 1 PMID: 22260203
Authors: Shultz, M. D. - Kirby, C. A. - Stams, T. - Chin, D. N. - Blank, J. - Charlat, O. - Cheng, H. - Cheung, A. - Cong, F. - Feng, Y. - Fortin, P. D. - Hood, T. - Tyagi, V. - Xu, M. - Zhang, B. - Shao, W.
Journal: J Med Chem

The Wnt signaling pathway is critical to the regulation of key cellular processes. When deregulated, it has been shown to play a crucial role in the growth and progression of multiple human cancers. The identification of small molecule modulators of Wnt signaling has proven challenging, largely due to the relative paucity of druggable nodes in this pathway. Several recent publications have identified small molecule inhibitors of the Wnt pathway, and tankyrase (TNKS) inhibition has been demonstrated to antagonize Wnt signaling via axin stabilization. Herein, we report the early hit assessment of a series of compounds previously reported to antagonize Wnt signaling. We report the biophysical, computational characterization, structure-activity relationship, and physicochemical properties of a novel series of [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazole inhibitors of TNKS1 and 2. Furthermore, a cocrystal structure of compound 24 complexed to TNKS1 demonstrates an alternate binding mode for PARP family member proteins that does not involve interactions with the nicotinamide binding pocket.

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Dual Targeting of Histone Deacetylase and Topoisomerase II with Novel Bifunctional Inhibitors.

Publication Date: 2012 Jan 19 PMID: 22260166
Authors: Guerrant, W. - Patil, V. - Canzoneri, J. C. - Oyelere, A. K.
Journal: J Med Chem

Strategies to ameliorate the flaws of current chemotherapeutic agents, while maintaining potent anticancer activity, are of particular interest. Agents which can modulate multiple targets may have superior utility and fewer side effects than current single-target drugs. To explore the prospect in cancer therapy of a bivalent agent that combines two complimentary chemo-active groups within a single molecular architecture; we have synthesized dual-acting histone deacetylase and topoisomerase II inhibitors. These dual-acting agents are derived from suberoylanilide hydroxamic acid (SAHA) and anthracycline daunorubicin; prototypical histone deacetylase (HDAC) and topoisomerase II (Topo II) inhibitors respectively. We report herein that these agents present the signatures of inhibition of HDAC and Topo II in both cell-free and whole cell assays. Moreover, these agents potently inhibit the proliferation of representative cancer cell lines.

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Targeting Peroxisome Proliferator-Activated Receptors (PPARs): development of modulators.

Publication Date: 2012 Jan 19 PMID: 22260081
Authors: Pirat, C. - Farce, A. - Lebegue, N. - Renault, N. - Furman, C. - Millet, R. - Yous, S. - Speca, S. - Berthelot, P. - Desreumaux, P. - Chavatte, P.
Journal: J Med Chem

This review covers the rapid progress in the functional analysis of the Peroxisome Proliferator-Activated Receptors (PPARs), which has led to a greater understanding of these receptors and has established them as molecular targets for the development of drugs against metabolic diseases. Natural and synthetic ligands for the three subtypes PPARalpha, PPARgamma and PPARbeta/delta, are reported: agonists or antagonists, partial or selective PPARs modulators (SPPARMs), dual agonists and pan-PPARalpha,gamma,beta/delta agonists. We conclude with the future of PPARs ligands research and the emergence of new hybrid compounds of the multitarget drug genre with a particular interest in the treatment of chronic inflammation.

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Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors.

Publication Date: 2012 Jan 18 PMID: 22257213
Authors: Singh, R. - Masuda, E. S. - Payan, D. G.
Journal: J Med Chem

Spleen tyrosine kinase (SYK) is a member of the cytoplasmic protein tyrosine kinase (PTK) family and has been identified as an important target for the development of therapeutics for the treatment of allergic and autoimmune diseases. Maladies resulting from chronic inflammation and autoimmune dysfunction include, asthma, rheumatoid arthritis (RA), Crohn's disease, systemic lupus erythematosus (SLE) and idiopathic thrombocytopenia purpura (ITP). SYK has garnered substantial attention because of its importance as a key signal transduction regulator through antigen and Fc receptors in hematopoietic cells. Recently SYK has entered the mainstream of potential pharmaceutical targets with a number of inhibitor classes being reported in the literature. The true potential as a validated target for inhibition by small molecules has been investigated in the last few years, with the emergence of advanced clinical trial data. Structurally SYK possesses a tandem N-terminal Src homology 2 domains (SH2), referred to as N-SH2 and C-SH2 domains, followed by a C-terminal kinase domain and most closely related to ZAP-70. The multiple phosphorylation sites on SYK are fundamental structural prerequisites for its diverse functional activity. Overall, these phosphorylation sites contribute to maintaining the kinase in an inactivated state. In addition, they are implicated in events leading to primary activation of the kinase catalytic domain, amplification of this activity, and the orchestrated phosphorylation of multiple substrates. Utilization of the numerous sites of phosphorylation on SYK leads to the activation of a multitude of signaling networks relevant to immune and autoimmune maladies. SYK serves as a master regulator of inflammatory responses in a multitude of immune cells and as a result, inhibiting SYK activity dampens inflammation broadly and comprehensively. The validation of SYK as an effective target for therapeutic intervention in autoimmune and inflammatory disorders has picked up pace over the last decade. In particular, this has been attributable to the recognition of key biological findings, coupled with successful small molecule inhibitors of SYK that have shown early indications of clinical efficacy in diverse autoimmune and inflammatory diseases. SYK as a target has gained reinforcement with the successful completion of several Phase 2 clinical studies in RA, ITP and B-cell lymphoma. Additional clinical studies are under way that may further emphasize the position of SYK as a therapeutically relevant target.

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Pyridone Methylsulfone Hydroxamate LpxC Inhibitors for the Treatment of Serious Gram-Negative Infections.

Publication Date: 2012 Jan 18 PMID: 22257165
Authors: Montgomery, J. I. - Brown, M. F. - Reilly, U. - Price, L. M. - Abramite, J. A. - Arcari, J. - Barham, R. A. - Che, Y. - Chen, J. M. - Chung, S. W. - Collantes, E. M. - Desbonnet, C. - Doroski, M. - Doty, J. - Engtrakul, J. J. - Harris, T. M. - Huband, M. - Knafels, J. D. - Leach, K. L. - Liu, S. - Marfat, A. - McAllister, L. A. - McElroy, E. - Menard, C. - Mitton-Fry, M. - Mullins, L. - Noe, M. C. - O'Donnell, J. P. - Oliver, R. - Penzien, J. - Plummer, M. - Shanmugasundaram, V. - Thoma, C. - Tomaras, A. P. - Uccello, D. P. - Vaz, A. D. - Wishka, D. G.
Journal: J Med Chem

The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.

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Testing the Promiscuity of Commercial Kinase Inhibitors against the AGC Kinase Group Using a Split-luciferase Screen.

Publication Date: 2012 Jan 18 PMID: 22257127
Authors: Jester, B. - Gaj, A. - Shomin, C. D. - Cox, K. J. - Ghosh, I.
Journal: J Med Chem

Abstract. Using a newly developed competitive binding assay dependent upon the reassembly of a split reporter protein, we have tested the promiscuity of a panel of reported kinase inhibitors against the AGC group. Many non-AGC targeted kinase inhibitors target multiple members of the AGC group. In general, structurally similar inhibitors consistently exhibited activity toward the same target as well as toward closely related kinases. The inhibition data was analyzed to test the predictive value of either using identity scores derived from residues within 6 A of the active site or identity scores derived from the entire kinase domain. The results suggest that the active site identity in certain cases may be a stronger predictor of inhibitor promiscuity. The overall results provide general guidelines for establishing inhibitor selectivity, as well as for the future design of inhibitors that either target or avoid AGC kinases.

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Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: a novel template for the design of highly selective A2B adenosine receptor antagonists.

Publication Date: 2012 Jan 18 PMID: 22257095
Authors: Taliani, S. - Pugliesi, I. - Barresi, E. - Simorini, F. - Salerno, S. - La Motta, C. - Marini, A. M. - Cosimelli, B. - Cosconati, S. - Di Maro, S. - Marinelli, L. - Daniele, S. - Trincavelli, M. L. - Greco, G. - Novellino, E. - Martini, C. - Da Settimo, F.
Journal: J Med Chem

In an effort to identify novel ligands possessing high affinity and selectivity for the A2B AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A1 AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A2B AR, no affinity at A3 AR, and various degrees of selectivity towards A1 and A2A ARs. Investigation of a new series featuring modified substituents at the 10-position (4'-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A2B AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A2A AR, conferring high A2B/A2A AR selectivity. Derivative 13 (X = Cl, R = C6H5) was the most potent and selective compound, with an IC50 of 3.10 nM at A2B AR and no affinity at A1, A2A and A3 ARs.

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CHEMICAL OPTIMIZATION OF NEW LIGANDS OF THE LOW-DENSITY LIPOPROTEIN RECEPTOR AS POTENTIAL VECTORS FOR CENTRAL NERVOUS SYSTEM TARGETING.

Publication Date: 2012 Jan 18 PMID: 22257077
Authors: Malcor, J. D. - Payrot, N. - David, M. - Faucon, A. - Abouzid, K. - Jacquot, G. - Floquet, N. - Debarbieux, F. - Rougon, G. - Martinez, J. - Khrestchatisky, M. - Vlieghe, P. - Lisowski, V.
Journal: J Med Chem

Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the CNS in a non-invasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross the BBB. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.

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5-IMINO-1,2,4-THIADIAZOLES: FIRST SMALL MOLECULES AS SUBSTRATE COMPETITIVE INHIBITORS OF GLYCOGEN SYNTHASE KINASE 3.

Publication Date: 2012 Jan 18 PMID: 22257026
Authors: Palomo, V. - Perez, D. I. - Perez, C. - Morales, J. A. - Soteras, I. - Alonso-Gil, S. - Encinas, A. - Castro, A. - Campillo, N. E. - Perez-Castillo, A. - Gil, C. - Martinez, A.
Journal: J Med Chem

Cumulative evidence strongly supports that glycogen synthase kinase-3 (GSK-3) is a pathogenic molecule when it is up-dysregulated emerging as an important therapeutic target in severe unmet human diseases. GSK-3 specific inhibitors might be promising effective drugs for the treatment of devastating pathologies such as neurodegenerative diseases, stroke and mood disorders. As GSK-3 has the ability to phosphorylate primed substrates, small molecules able to bind to this site should be perfect drug candidates, able to partially block the activity of the enzyme over some specific substrates. Here, we report substituted 5-imino-1,2,4-thiadiazoles as the first small molecules able to inhibit GSK-3 in a substrate competitive manner. These compounds are cell permeable, able to decrease inflammatory activation and to selectively differentiate neural stem cells. Overall, 5-imino-1,2,4-thiadiazoles are presented here as new molecules able to decrease neuronal cell death and to increase endogenous neurogenesis blocking the GSK-3 substrate site.

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Minimization of relaxin-3 leading to high affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1.

Publication Date: 2012 Jan 18 PMID: 22257012
Authors: Shabanpoor, F. - Hossain, M. A. - Ryan, P. J. - Belgi, A. - Layfield, S. - Kocan, M. - Zhang, S. - Samuel, C. S. - Gundlach, A. L. - Bathgate, R. A. - Separovic, F. - Wade, J. D.
Journal: J Med Chem

Relaxin-3 is a neuropeptide that is implicated in the regulation of stress responses and memory. The elucidation of its precise physiological role(s) has, however, been hampered by cross-activation of the relaxin-2 receptor, RXFP1, in the brain. The current study undertook to develop analogues of human relaxin-3 (H3 relaxin) that can selectively bind and activate its receptor, RXFP3. We developed a high affinity selective agonist (analogue 2) by removal of the intra-A-chain disulfide bond and deletion of ten residues from the N-terminus of the A-chain. Further truncation of this analogue from the C-terminus of the B-chain to Cys^B22 and addition of an Arg^B23 led to a high affinity, RXFP3-selective, competitive antagonist (analogue 3). Central administration of analogue 2 in rats increased food intake, which was blocked by prior co-administration of analogue 3. These novel RXFP3-selective peptides represent valuable pharmacological tools to study the physiological roles of H3 relaxin/RXFP3 systems in the brain and important leads for the development of novel compounds for treatment of affective and cognitive disorders.

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Identification of Novel Adenosine A_2A Receptor Antagonists by Virtual Screening.

Publication Date: 2012 Jan 17 PMID: 22250781
Authors: Langmead, C. J. - Andrews, S. P. - Congreve, M. - Errey, J. C. - Hurrell, E. - Marshall, F. H. - Mason, J. S. - Richardson, C. M. - Robertson, N. - Zhukov, A. - Weir, M.
Journal: J Med Chem

Virtual screening was performed against experimentally enabled homology models of the adenosine A_2A receptor, identifying a diverse range of ligand efficient antagonists (hit rate 9%). Using ligand docking and Biophysical Mapping^TM (BPM) two of the hits identified (1 and 5) were optimised to potent and selective lead molecules (from 5: 11-13; pK_I values 7.5 - 8.5; 13 to >100-fold selective versus adenosine A₁; from 1: 14-16; pK_I values 7.9 - 9.0; 19 to 59-fold selective).

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Structure-activity Relationship of Novel Menequinone-4 Analogues: Modification of the Side Chain affects their Biological Activities.

Publication Date: 2012 Jan 17 PMID: 22250752
Authors: Suhara, Y. - Hanada, N. - Okitsu, T. - Sakai, M. - Watanabe, M. - Nakagawa, K. - Wada, A. - Takeda, K. - Takahashi, K. - Tokiwa, H. - Okano, T.
Journal: J Med Chem

WWe synthesized new vitamin K analogues with demethylation or reduction of the double bonds of the side chain of menaquinone-4 (MK-4), and evaluated their SXR-mediated transcriptional activity as well as the extent of their conversion to MK-4. The results indicated that the analogue with the methyl group deleted at the 7' site of the side chain part affected conversion activity to MK-4. In contrast, a decrease in the number of the double bonds in the side chain moiety appeared to decrease the SXR-mediated transcriptional activity.

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Directed R-Group Combination Graph: A Methodology To Uncover Structure-Activity Relationship Patterns in a Series of Analogues.

Publication Date: 2012 Jan 27 PMID: 22248436
Authors: Wassermann, A. M. - Bajorath, J.
Journal: J Med Chem

A graphical method is introduced to study details of structure-activity relationships (SARs) in analogue series that further extends conventional analysis of analogues using R-group tables or related approaches and that provides additional and more differentiated SAR information. The newly designed graph structure represents entire series of analogues in a consistent manner, regardless of their size and complexity of substitution patterns. The approach is specifically tailored toward a systematic exploration and intuitive interpretation of SAR features involving different R-groups and their combinations. Analogues and their potency information are systematically organized on the basis of R-group combinations that are present in a series. This organization scheme results in graph components that represent well-defined SAR patterns. Analysis of these patterns provides an immediate access to critical substitution sites and R-group combinations, favorable and unfavorable R-groups, or nonadditive potency effects of multisite substitutions. Furthermore, the data structure makes it possible to design new analogues by combining favorable R-group combinations derived from different compounds.

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An aberrant cyclization affords a C-6 modified cyclic adenosine 5'-diphosphoribose analog with biological activity in Jurkat T cells.

Publication Date: 2012 Jan 16 PMID: 22248391
Authors: Moreau, C. - Kirchberger, T. - Zhang, B. - Thomas, M. P. - Weber, K. - Guse, A. H. - Potter, B. V.
Journal: J Med Chem

Two nicotinamide adenine dinucleotide (NAD+) analogs modified at the 6 position of the purine ring were synthesized, and their substrate properties towards Aplysia californica ADP-ribosyl cyclase investigated. 6-N-Methyl NAD+ (6-N-Methyl nicotinamide adenosine 5'-dinucleotide 10) hydrolyzes to give the linear 6-N-methyl ADPR (adenosine 5'-diphosphoribose, 11), whereas 6-thio NHD+ (6-thio nicotinamide hypoxanthine 5'-dinucleotide, 17) generates a cyclic dinucleotide. Surprisingly, NMR correlation spectra confirm this compound to be the N1 cyclic product 6-thio N1-cIDPR (6-thio cyclic inosine 5'-diphosphoribose, 3), although the corresponding 6-oxo analog is well known to cyclize at N7. In Jurkat T cells, the parent cyclic inosine 5'-diphosphoribose N1-cIDPR 2, 6-thio N1-cIDPR antagonizes both cADPR- and N1-cIDPR- induced Ca2+ release, but possesses weak agonist activity at higher concentration. 3 is thus identified as the first C-6 modified cADPR (cyclic adenosine 5'-diphosphoribose) analog antagonist, represents the first example of a fluorescent N1-cyclized cADPR analog and is a new pharmacological tool for intervention in the cADPR pathway of cellular signaling.

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Design of barbiturate-nitrate hybrids that inhibit MMP-9 activity and secretion.

Publication Date: 2012 Jan 16 PMID: 22248361
Authors: Wang, J. - O'Sullivan, S. - Harmon, S. - Keaveny, R. - Radomski, M. W. - Medina, C. - Gilmer, J. F.
Journal: J Med Chem

We describe a new type of barbiturate-based matrix metalloproteinase (MMP) inhibitor incorporating a nitric oxide (NO) donor/mimetic group (Series 1). The compounds were designed to inhibit MMP at enzyme level and to attenuate MMP-9 secretion arising from inflammatory signalling. In order to detect effects related to the nitrate, we prepared and studied an analogous series of barbiturate C5-alkyl alcohols that were unable to release NO (Series 2). Both series inhibited recombinant human MMP-2/9 activity with nanomolar potency. Series 1 consistently inhibited the secretion of MMP-9 from TNF/IL1 stimulated Caco-2 cells at 10 M, which could be attributed to NO related effects because the non-nitrate panel did not affect enzyme levels. Several compounds from Series 1 (10 M) inhibited tumour cell invasion but none from the non-nitrate panel did. The work shows that MMP-inhibitory barbiturates are suitable scaffolds for hybrid design, targeting additional facets of MMP pathophysiology, with potential to improve risk-benefit ratios.

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Contribution of Phosphates and Adenine to the Potency of Adenophostins at the IP3 Receptor: Synthesis of all Possible Bisphosphates of Adenophostin A.

Publication Date: 2012 Jan 16 PMID: 22248345
Authors: Sureshan, K. M. - Riley, A. M. - Thomas, M. P. - Tovey, S. C. - Taylor, C. W. - Potter, B. V.
Journal: J Med Chem

Though adenophostin A (AdA), the most potent agonist of D-myo-inositol 1,4,5-trisphosphate receptors (IP3R), is thought to mimic IP3, the relative roles of the different phosphate groups and the adenosine motif have not been established. We synthesized all three possible bisphosphate analogues of AdA and glucose 3,4-bisphosphate (7, AdA lacking the 2-AMP). 2'-Dephospho-AdA (6) was prepared via a novel regioselective dephosphorylation strategy. Assessment of the abilities of these bisphosphates to stimulate intracellular Ca2+ release using recombinant rat type 1 IP3R (IP3R1) revealed that 6, a mimic of Ins(4,5)P2, is only 4-fold less potent than IP3, while 7 is some 400-fold weaker and even 3"-dephospho-AdA (5) is measurably active, despite missing one of the vicinal bisphosphate groups normally thought to be crucial for IP3-like activity. Compound 6 is the most potent bisphosphate yet discovered with activity at IP3R. Thus, adenosine has a direct role independent of the 2'-phosphate group in contributing towards the potency of adenophostins, the vicinal bisphosphate motif is not essential for activity at the IP3R, as always thought, and it is possible to design potent agonists with just two of the three phosphates. A model with a possible adenine-R504 interaction supports the unusually potent activity of 2"-phospho-3"-dephospho-AdA and allows a reappraisal of the unexpected activity reported for the AdA regioisomer 2"-phospho-3"-dephospho-AdA 40.

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From the First Selective Nonpeptide AT2 Receptor Agonist to Structurally Related Antagonists.

Publication Date: 2012 Jan 16 PMID: 22248302
Authors: Murugaiah, A. M. - Wu, X. - Wallinder, C. - Mahalingam, A. K. - Wan, Y. - Skold, C. - Botros, M. - Guimond, M. O. - Joshi, A. - Nyberg, F. J. - Gallo-Payet, N. - Hallberg, A. - Alterman, M.
Journal: J Med Chem

ABSTRACT A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT2 receptor agonist M024/C21 (1) and all the non-peptidic AT2 receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT1 and AT2 receptors. A high AT2/AT1 receptor selectivity was obtained with all 41 compounds synthesized and the majority exhibited Ki values ranging from 2 nM to 100 nM. Five compounds were evaluated for their functional activity at the AT2 receptor, applying a neurite outgrowth assay in NG108-15 cells. Notably, four of the five compounds, with representatives from both series, acted as potent AT2 receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT2 receptor antagonist used in most laboratories. No AT2 receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT2 receptor in more complex physiological models.

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Triphenylbutanamines - Kinesin Spindle Protein inhibitors with in vivo anti-tumour activity.

Publication Date: 2012 Jan 16 PMID: 22248262
Authors: Wang, F. - Good, J. A. - Rath, O. - Kaan, H. Y. - Sutcliffe, O. B. - Mackay, S. P. - Kozielski, F.
Journal: J Med Chem

The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-L-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit Kiapp values
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Diverse Heterocyclic Scaffolds as Allosteric Inhibitors of AKT.

Publication Date: 2012 Jan 27 PMID: 22248236
Authors: Kettle, J. G. - Brown, S. - Crafter, C. - Davies, B. R. - Dudley, P. - Fairley, G. - Faulder, P. - Fillery, S. - Greenwood, H. - Hawkins, J. - James, M. - Johnson, K. - Lane, C. D. - Pass, M. - Pink, J. H. - Plant, H. - Cosulich, S. C.
Journal: J Med Chem

Wide-ranging exploration of potential replacements for a quinoline-based inhibitor of activation of AKT kinase led to number of alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, and one such compound demonstrated pharmacodynamic knockdown of phosphorylation of AKT and downstream biomarkers in vivo and inhibition of tumor growth in a breast cancer xenograft model.

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A Novel Class of Highly Potent Irreversible Hepatitis C Virus (HCV) NS5B Polymerase Inhibitors.

Publication Date: 2012 Jan 16 PMID: 22247956
Authors: Chen, K. X. - Lesburg, C. A. - Vibulbhan, B. - Yang, W. - Chan, T. Y. - Venkatraman, S. - Velazquez, F. - Zeng, Q. - Bennett, F. - Anilkumar, G. N. - Duca, J. - Jiang, Y. - Pinto, P. - Wang, L. - Huang, Y. - Selyutin, O. - Gavalas, S. - Pu, H. - Agrawal, S. - Feld, B. - Huang, H. C. - Li, C. - Cheng, K. C. - Shih, N. Y. - Kozlowski, J. A. - Rosenblum, S. B. - Njoroge, F. G.
Journal: J Med Chem

Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with para-fluoro-sulfone- or para-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC50 = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 SAR investigation demonstrated that small alkyl groups were preferred. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 muM.h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.

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Homobivalent Ligands of the Atypical Antipsychotic Clozapine: Design, Synthesis, and Pharmacological Evaluation.

Publication Date: 2012 Feb 2 PMID: 22243698
Authors: McRobb, F. M. - Crosby, I. T. - Yuriev, E. - Lane, J. R. - Capuano, B.
Journal: J Med Chem

To date all typical and atypical antipsychotics target the dopamine D(2) receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D(2) receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D(2) receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.

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Trivalent Ultrashort Lipopeptides are Potent pH Dependent Antifungal Agents.

Publication Date: 2012 Feb 1 PMID: 22243686
Authors: Arnusch, C. J. - Albada, H. B. - van Vaardegem, M. - Liskamp, R. M. - Sahl, H. G. - Shadkchan, Y. - Osherov, N. - Shai, Y.
Journal: J Med Chem

The activity of antimicrobial peptides (AMPs) that contain a large proportion of histidine residues (pK(a) approximately 6) depends on the physiological pH environment. Advantages of these AMPs include high activity in slightly acidic areas of the human body and relatively low toxicity in other areas. Also, many AMPs are highly active in a multivalent form, but this often increases toxicity. Here we designed pH dependent amphiphilic compounds consisting of multiple ultrashort histidine lipopeptides on a triazacyclophane scaffold, which showed high activity toward Aspergillus fumigatus and Cryptococcus neoformans at acidic pH, yet remained nontoxic. In vivo, treatment with a myristic acid conjugated trivalent histidine-histidine dipeptide resulted in 55% survival of mice (n = 9) in an otherwise lethal murine lung Aspergillus infection model. Fungal burden was assessed and showed completely sterile lungs in 80% of the mice (n = 5). At pH 5.5 and 7.5, differing peptide-membrane interactions and peptide nanostructures were observed. This study underscores the potential of unique AMPs to become the next generation of clinical antimicrobial therapy.

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New Tacrine-4-Oxo-4H-chromene Hybrids as Multifunctional Agents for the Treatment of Alzheimer's Disease, with Cholinergic, Antioxidant, and beta-Amyloid-Reducing Properties.

Publication Date: 2012 Jan 27 PMID: 22243648
Authors: Fernandez-Bachiller, M. I. - Perez, C. - Monjas, L. - Rademann, J. - Rodriguez-Franco, M. I.
Journal: J Med Chem

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and beta-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.

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3-Fluoro- and 3,3-Difluoro-3,4-dideoxy-KRN7000 Analogues as New Potent Immunostimulator Agents: Total Synthesis and Biological Evaluation in Human Invariant Natural Killer T Cells and Mice.

Publication Date: 2012 Feb 1 PMID: 22243602
Authors: Hunault, J. - Diswall, M. - Frison, J. C. - Blot, V. - Rocher, J. - Marionneau-Lambot, S. - Oullier, T. - Douillard, J. Y. - Guillarme, S. - Saluzzo, C. - Dujardin, G. - Jacquemin, D. - Graton, J. - Le Questel, J. Y. - Evain, M. - Lebreton, J. - Dubreuil, D. - Le Pendu, J. - Pipelier, M.
Journal: J Med Chem

We propose here the synthesis and biological evaluation of 3,4-dideoxy-GalCer derivatives. The absence of the 3- and 4-hydroxyls on the sphingoid base is combined with the introduction of mono or difluoro substituent at C3 (analogues 8 and 9, respectively) to evaluate their effect on the stability of the ternary CD1d/GalCer/TCR complex which strongly modulate the immune responses. Biological evaluations were performed in vitro on human cells and in vivo in mice and results discussed with support of modeling studies. The fluoro 3,4-dideoxy-GalCer analogues appears as partial agonists compared to KRN7000 for iNKT cell activation, inducing T(H)1 or T(H)2 biases that strongly depend of the mode of antigen presentation, including human vs mouse differences. We evidenced that if a sole fluorine atom is not able to balance the loss of the 3-OH, the presence of a difluorine group at C3 of the sphingosine can significantly restore human iNKT activation.

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Synthesis and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl regioisomers as inhibitors of de novo purine biosynthesis with selectivity for cellular uptake by high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier.

Publication Date: 2012 Jan 13 PMID: 22243528
Authors: Wang, L. - Cherian, C. - Desmoulin, S. K. - Mitchell-Ryan, S. - Hou, Z. - Matherly, L. H. - Gangjee, A.
Journal: J Med Chem

ABSTRACT We reported the selective transport of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a 3- (3a) and 4-carbon (3b) bridge. Compound 3a was more potent than 3b against tumor cells; While 3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over reduced folate carrier (RFC), 3a was not. To determine if decreasing the distance between the bicyclic scaffold and L-glutamate in 3b would preserve transport selectivity and potency against human tumor cells, 3b regioisomers with [1,3] (7 and 8) and [1,2] (4, 5 and 6) substitutions on the thienoyl ring, and with acetylenic insertions in the 4-atom bridge, were synthesized and evaluated. Compounds 7 and 8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FRalpha and PCFT over RFC.

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1,4-Dioxane, a Suitable Scaffold for the Development of Novel M(3) Muscarinic Receptor Antagonists.

Publication Date: 2012 Feb 2 PMID: 22243489
Authors: Del Bello, F. - Barocelli, E. - Bertoni, S. - Bonifazi, A. - Camalli, M. - Campi, G. - Giannella, M. - Matucci, R. - Nesi, M. - Pigini, M. - Quaglia, W. - Piergentili, A.
Journal: J Med Chem

In this study the modulation of the pharmacological profile from agonist to antagonist was successfully obtained by replacing the methyl group in position 6 of the 1,4-dioxane scaffold of the potent M(2)/M(3) muscarinic agonist 1 with bulkier groups. In particular, the 6,6-diphenyl substitution provided the potent M(3) preferring antagonist (+/-)-17, which in in vivo study proved to be effective in reducing the volume-induced contractions of rat urinary bladder and was devoid of cardiovascular effects.

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Structure Guided Development of Novel Thymidine Mimetics Targeting Pseudomonas aeruginosa Thymidylate Kinase: From Hit to Lead Generation.

Publication Date: 2012 Jan 26 PMID: 22243413
Authors: Choi, J. Y. - Plummer, M. S. - Starr, J. - Desbonnet, C. R. - Soutter, H. - Chang, J. - Miller, J. R. - Dillman, K. - Miller, A. A. - Roush, W. R.
Journal: J Med Chem

Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogues, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (1, IC(50) = 58 muM), which has reasonable inhibition potency against Pseudomonas aeruginosa TMK (PaTMK), was identified by the analysis of the binding mode of thymidine or TP(5)A in a PaTMK homology model. This hit (1) was cocrystallized with PaTMK, and several potent PaTMK inhibitors (leads, 46, 47, 48, and 56, IC(50) = 100-200 nM) were synthesized using computer-aided design approaches including virtual synthesis/screening, which was used to guide the design of inhibitors. The binding mode of the optimized leads in PaTMK overlaps with that of other bacterial TMKs but not with human TMK, which shares few common features with the bacterial enzymes. Therefore, the optimized TMK inhibitors described here should be useful for the development of antibacterial agents targeting TMK without undesired off-target effects. In addition, an inhibition mechanism associated with the LID loop, which mimics the process of phosphate transfer from ATP to dTMP, was proposed based on X-ray cocrystal structures, homology models, and structure-activity relationship results.

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Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Recptor 1 Agonists.

Publication Date: 2012 Jan 16 PMID: 22242551
Authors: Negoro, N. - Sasaki, S. - Ito, M. - Kitamura, S. - Tsujihata, Y. - Ito, R. - Suzuki, M. - Takeuchi, K. - Suzuki, N. - Miyazaki, J. - Santou, T. - Odani, T. - Kanzaki, N. - Funami, M. - Tanaka, T. - Yasuma, T. - Momose, Y.
Journal: J Med Chem

The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to beta-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro -1-benzofuran-3-yl)acetic acid) which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.

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Ligand-Based Design of a Potent and Selective Inhibitor of Cytochrome P450 2C19.

Publication Date: 2012 Jan 31 PMID: 22239545
Authors: Foti, R. S. - Rock, D. A. - Han, X. - Flowers, R. A. - Wienkers, L. C. - Wahlstrom, J. L.
Journal: J Med Chem

A series of omeprazole-based analogues was synthesized and assessed for inhibitory activity against CYP2C19. The data was used to build a CYP2C19 inhibition pharmacophore model for the series. The model was employed to design additional analogues with inhibitory potency against CYP2C19. Upon identifying inhibitors of CYP2C19, ligand-based design shifted to attenuating the rapid clearance observed for many of the inhibitors. While most analogues underwent metabolism on their aliphatic side chain, metabolite identification indicated that for analogues such as compound 30 which contain a heterocycle adjacent to the sulfur moiety, metabolism primarily occurred on the benzimidazole moiety. Compound 30 exhibited improved metabolic stability (Cl(int) = 12.4 mL/min/nmol) and was selective in regard to inhibition of CYP2C19-catalyzed (S)-mephenytoin hydroxylation in human liver microsomes. Finally, representative compounds were docked into a homology model of CYP2C19 in an effort to understand the enzyme-ligand interactions that may lead to favorable inhibition or metabolism properties.

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A Synthetic Chalcone as a Potent Inducer of Glutathione Biosynthesis.

Publication Date: 2012 Jan 30 PMID: 22239485
Authors: Kachadourian, R. - Day, B. J. - Pugazhenti, S. - Franklin, C. C. - Genoux-Bastide, E. - Mahaffey, G. - Gauthier, C. - Di Pietro, A. - Boumendjel, A.
Journal: J Med Chem

Chalcones continue to attract considerable interest due to their anti-inflammatory and antiangiogenic properties. We recently reported the ability of 2',5'-dihydroxychalcone (2',5'-DHC) to induce both breast cancer resistance protein-mediated export of glutathione (GSH) and c-Jun N-terminal kinase-mediated increased intracellular GSH levels. Herein, we report a structure-activity relationship study of a series of 30 synthetic chalcone derivatives with hydroxyl, methoxyl, and halogen (F and Cl) substituents and their ability to increase intracellular GSH levels. This effect was drastically improved with one or two electrowithdrawing groups on phenyl ring B and up to three methoxyl and/or hydroxyl groups on phenyl ring A. The optimal structure, 2-chloro-4',6'-dimethoxy-2'-hydroxychalcone, induced both a potent NF-E2-related factor 2-mediated transcriptional response and an increased formation of glutamate cysteine ligase holoenzyme, as shown using a human breast cancer cell line stably expressing a luciferase reporter gene driven by antioxidant response elements.

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Design and Characterization of Optimized Adenosine A(2A)/A(1) Receptor Antagonists for the Treatment of Parkinson's Disease.

Publication Date: 2012 Jan 26 PMID: 22239465
Authors: Shook, B. C. - Rassnick, S. - Wallace, N. - Crooke, J. - Ault, M. - Chakravarty, D. - Barbay, J. K. - Wang, A. - Powell, M. T. - Leonard, K. - Alford, V. - Scannevin, R. H. - Carroll, K. - Lampron, L. - Westover, L. - Lim, H. K. - Russell, R. - Branum, S. - Wells, K. M. - Damon, S. - Youells, S. - Li, X. - Beauchamp, D. A. - Rhodes, K. - Jackson, P. F.
Journal: J Med Chem

The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.

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Toll-Like Receptor (TLR)-7 and -8 Modulatory Activities of Dimeric Imidazoquinolines.

Publication Date: 2012 Jan 27 PMID: 22239408
Authors: Shukla, N. M. - Mutz, C. A. - Malladi, S. S. - Warshakoon, H. J. - Balakrishna, R. - David, S. A.
Journal: J Med Chem

Toll-like receptors (TLRs) are pattern recognition receptors that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but are structurally distinct from host molecules. The TLR7-agonistic imidazoquinolines are of interest as vaccine adjuvants given their ability to induce pronounced Th1-skewed humoral responses. Minor modifications on the imidazoquinoline scaffold result in TLR7-antagonistic compounds which may be of value in addressing innate immune activation-driven immune exhaustion observed in HIV. We describe the syntheses and evaluation of TLR7 and TLR8 modulatory activities of dimeric constructs of imidazoquinoline linked at the C2, C4, C8, and N(1)-aryl positions. Dimers linked at the C4, C8, and N(1)-aryl positions were agonistic at TLR7; only the N(1)-aryl dimer with a 12-carbon linker was dual TLR7/8 agonistic. Dimers linked at C2 position showed antagonistic activities at TLR7 and TLR8; the C2 dimer with a propylene spacer was maximally antagonistic at both TLR7 and TLR8.

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Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency.

Publication Date: 2012 Jan 26 PMID: 22239250
Authors: Borthwick, A. D. - Liddle, J. - Davies, D. E. - Exall, A. M. - Hamlett, C. - Hickey, D. M. - Mason, A. M. - Smith, I. E. - Nerozzi, F. - Peace, S. - Pollard, D. - Sollis, S. L. - Allen, M. J. - Woollard, P. M. - Pullen, M. A. - Westfall, T. D. - Stanislaus, D. J.
Journal: J Med Chem

A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2',6'-dimethyl-3'-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK(i) = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.

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Rational Approaches to Improving Selectivity in Drug Design.

Publication Date: 2012 Jan 12 PMID: 22239221
Authors: Huggins, D. J. - Sherman, W. - Tidor, B.
Journal: J Med Chem

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Exploring Activity Cliffs in Medicinal Chemistry.

Publication Date: 2012 Jan 27 PMID: 22236250
Authors: Stumpfe, D. - Bajorath, J.
Journal: J Med Chem

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Synthesis and Evaluation of (18)F-Labeled Styryltriazole and Resveratrol Derivatives for beta-Amyloid Plaque Imaging.

Publication Date: 2012 Jan 26 PMID: 22236086
Authors: Lee, I. - Choe, Y. S. - Choi, J. Y. - Lee, K. H. - Kim, B. T.
Journal: J Med Chem

In the present study, a styryltriazole and four resveratrol derivatives were synthesized as candidates for beta-amyloid (Abeta) plaque imaging. On the basis of their binding affinities to Abeta(1-42) aggregates, the styryltriazole (1, K(i) = 12.8 nM) and one resveratrol derivative (5, K(i) = 0.49 nM) were labeled with (18)F. In normal mice, tissue distribution of [(18)F]5 showed good initial brain uptake (3.26% ID/g at 2 min) but slow wash-out from brains (2-to-60 min uptake ratio: 2.9). Furthermore, it underwent in vivo metabolic defluorination (1.88% ID/g at 2 min and 9.73% ID/g at 60 min). In contrast, [(18)F]1 displayed high initial brain uptake (5.38% ID/g at 2 min) with rapid wash-out from brains (0.52% ID/g at 60 min; 2-to-60 min uptake ratio: 10.3). These results indicate that [(18)F]1 has in vivo kinetics comparable to PET radiopharmaceuticals currently under commercial development, demonstrating that [(18)F]1 is a desirable PET radioligand for Abeta plaque imaging.

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Structural Basis of Selective Inhibition of Human Tankyrases.

Publication Date: 2012 Jan 25 PMID: 22233320
Authors: Narwal, M. - Venkannagari, H. - Lehtio, L.
Journal: J Med Chem

Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a byproduct, nicotinamide, and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induces specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop, and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does not bind to the widely utilized nicotinamide-binding site makes the structure valuable for development of PARP inhibitors in general.

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Binding Evaluation of Fragment-Based Scaffolds for Probing Allosteric Enzymes.

Publication Date: 2012 Jan 24 PMID: 22229710
Authors: Krimm, I. - Lancelin, J. M. - Praly, J. P.
Journal: J Med Chem

Fragment-based drug discovery has become a powerful method for the generation of drug leads against therapeutic targets. Beyond the identification of novel and effective starting points for drug design, fragments have emerged as reliable tools for assessing protein druggability and identifying protein hot spots. Here, we have examined fragments resulting from the deconstruction of known inhibitors from the glycogen phosphorylase enzyme, a therapeutic target against type 2 diabetes, with two motivations. First, we have analyzed the fragment binding to the multiple binding sites of the glycogen phosphorylase, and then we have investigated the use of fragments to study allosteric enzymes. The work we report illustrates the power of fragmentlike ligands not only for probing the various binding pockets of proteins, but also for uncovering cooperativity between these various binding sites.

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Synthesis and Structure-Activity Relationships of (Aryloxy)quinazoline Ureas as Novel, Potent, and Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitors.

Publication Date: 2012 Jan 25 PMID: 22229669
Authors: Garofalo, A. - Farce, A. - Ravez, S. - Lemoine, A. - Six, P. - Chavatte, P. - Goossens, L. - Depreux, P.
Journal: J Med Chem

In our continuing search for medicinal agents to treat proliferative diseases, quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitors. A quantitative structure-activity relationship analysis was conducted to rationalize the structure-activity relationship and to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis of new compounds. A series of N-(aromatic)-N'-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}urea were identified as potent and selective inhibitors of the tyrosine kinase activity of VEGFR-2 (fetal liver kinase 1, kinase insert domain-containing receptor). An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. Substitution of diarylurea, competitive with ATP, afforded several analogues with low nanomolar inhibition of enzymatic activity of VEGFR-2. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of the series.

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Design, Synthesis, and Biological Evaluation of New Diaminoquinazolines as beta-Catenin/Tcf4 Pathway Inhibitors.

Publication Date: 2012 Jan 24 PMID: 22229647
Authors: Mao, Y. - Lin, N. - Tian, W. - Han, X. - Han, X. - Huang, Z. - An, J.
Journal: J Med Chem

More than 50 new diaminoquinazoline derivatives have been synthesized and evaluated in a colon carcinoma cell growth inhibition assay using HCT116 and SW480 cells. Twenty compounds with good cell growth inhibitory activities (<4 muM) were tested as inhibitors of the beta-catenin/T cell transcription factor 4 (Tcf4) signaling pathway using a HCT116 cell-based luciferase reporter assay. Results from the biological activities as well as the comparative molecular field analysis (CoMFA) of the properties of the molecules yielded a preliminary structure-activity relationship (SAR). Three potent compounds, 74, 78, and 86, showed IC(50) values <1 muM for growth inhibition of HCT116 cells and approximately 1 muM for SW480 cells, as well as IC(50) values of 1.5-2.5 muM for HCT116 cells with the luciferase reporter assay.

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Impact of Lipophilic Efficiency on Compound Quality.

Publication Date: 2012 Jan 24 PMID: 22229549
Authors: Tarcsay, A. - Nyiri, K. - Keseru, G. M.
Journal: J Med Chem

Lipophilic efficiency indices such as LLE and LELP were suggested to support balanced optimization of potency and ADMET profile. Here we investigated the performance of LLE and LELP on multiple data sets representing different stages of drug discovery including fragment and HTS hits and leads, development candidates, phase II compounds, and launched drugs. Analyzing their impact on ADME and safety properties and binding thermodynamics, we found that both LLE and LELP help identifying better quality compounds. LLE is sensible for the development stages but does not prefer fragment-type hits, while LELP has an advantage for this class of compounds and discriminates preferred starting points effectively. Both LLE and LELP have significant impact on ADME and safety profiles; however, LELP outperforms LLE in risk assessment at least on the present data set. On the basis of the results reported here, monitoring lipophilic efficiency metrics could contribute significantly to compound quality and might improve the output of medicinal chemistry programs.

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Structure-Activity Relationship Study of Opiorphin, a Human Dual Ectopeptidase Inhibitor with Antinociceptive Properties.

Publication Date: 2012 Jan 25 PMID: 22224710
Authors: Rosa, M. - Arsequell, G. - Rougeot, C. - Calle, L. P. - Marcelo, F. - Pinto, M. - Centeno, N. B. - Jimenez-Barbero, J. - Valencia, G.
Journal: J Med Chem

Toward developing new potential analgesics, this first structure-activity relationship study of opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH), a human peptide inhibiting enkephalin degradation, was performed. A systematic Ala scanning proved that Phe(3) is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalinase inhibition. A series of Phe(3)-halogenated analogues revealed that halogen bonding based optimization strategies are not applicable to this residue. Additional substituted Phe(3) derivatives showed that replacing l-Phe(3) for d-Phe(3) increased the AP-N inhibition potency by 1 order of magnitude. NMR studies and molecular mechanics calculations indicated that the improved potency may be due to CH-pi stacking interactions between the aromatic ring of d-Phe(3) and the Hgamma protons of Arg(2). This structural motif is not possible for the native opiorphin and may be useful for the design of further potent and metabolically stable analogues.

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Update on the development of antagonists of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). From lead optimization to clinical proof-of-concept in asthma and allergic rhinitis.

Publication Date: 2012 Jan 6 PMID: 22224640
Authors: Pettipher, R. - Whittaker, M.
Journal: J Med Chem

Since the discovery of PGD2 as the ligand for CRTH2 in 2001 there has been significant progress in defining the role of this receptor in allergic response and the identification of small molecular weight antagonists with drug-like properties. With ramatroban, indomethacin and various high throughput screening hits as starting points for medicinal chemistry programmes, a number of companies have identified lipophilic carboxylic acids as highly potent and selective CRTH2 antagonists. Early proof-of-concept clinical studies indicate that CRTH2 antagonists are effective in treating the signs and symptoms of both asthma and allergic rhinitis and possess features that are differentiated from existing therapies for these indications. It seems likely that CRTH2 antagonists will ultimately find utility as novel anti-allergic drugs, the challenge is to identify compounds that are effective when dosed once a day and prove to have an acceptable safety profile in long term studies.

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Discovery and Structure-Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington's Disease.

Publication Date: 2012 Jan 27 PMID: 22224594
Authors: Prime, M. E. - Andersen, O. A. - Barker, J. J. - Brooks, M. A. - Cheng, R. K. - Toogood-Johnson, I. - Courtney, S. M. - Brookfield, F. A. - Yarnold, C. J. - Marston, R. W. - Johnson, P. D. - Johnsen, S. F. - Palfrey, J. J. - Vaidya, D. - Erfan, S. - Ichihara, O. - Felicetti, B. - Palan, S. - Pedret-Dunn, A. - Schaertl, S. - Sternberger, I. - Ebneth, A. - Scheel, A. - Winkler, D. - Toledo-Sherman, L. - Beconi, M. - Macdonald, D. - Munoz-Sanjuan, I. - Dominguez, C. - Wityak, J.
Journal: J Med Chem

Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.

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Molecular Determinants of AcrB-Mediated Bacterial Efflux Implications for Drug Discovery.

Publication Date: 2012 Jan 27 PMID: 22224562
Authors: Manchester, J. I. - Buurman, E. T. - Bisacchi, G. S. - McLaughlin, R. E.
Journal: J Med Chem

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VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia.

Publication Date: 2012 Jan 26 PMID: 22221201
Authors: Heidary, D. K. - Huang, G. - Boucher, D. - Ma, J. - Forster, C. - Grey, R. - Xu, J. - Arnost, M. - Choquette, D. - Chen, G. - Zhou, J. H. - Yao, Y. M. - Ball, E. D. - Namchuk, M. - Davies, R. J. - Henkel, G.
Journal: J Med Chem

In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K(i) values of <1 nM and a cellular IC(50) between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.

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Discovery of 1,2,4-Triazine Derivatives as Adenosine A(2A) Antagonists using Structure Based Drug Design.

Publication Date: 2012 Jan 27 PMID: 22220592
Authors: Congreve, M. - Andrews, S. P. - Dore, A. S. - Hollenstein, K. - Hurrell, E. - Langmead, C. J. - Mason, J. S. - Ng, I. W. - Tehan, B. - Zhukov, A. - Weir, M. - Marshall, F. H.
Journal: J Med Chem

Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A(2A) receptor. The X-ray crystal structures of compounds 4e and 4g bound to the GPCR illustrate that the molecules bind deeply inside the orthosteric binding cavity. In vivo pharmacokinetic and efficacy data for compound 4k are presented, demonstrating the potential of this series of compounds for the treatment of Parkinson's disease.

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Discovery and Synthesis of Hydronaphthoquinones as Novel Proteasome Inhibitors.

Publication Date: 2012 Jan 5 PMID: 22220566
Authors: Ge, Y. - Kazi, A. - Marsilio, F. - Luo, Y. - Jain, S. - Brooks, W. - Daniel, K. G. - Guida, W. C. - Sebti, S. M. - Lawrence, H.
Journal: J Med Chem

ABSTRACT: Screening efforts led to the identification of PI-8182 (1), an inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. Compound 1 contains a hydronaphthoquinone pharmacophore with a thioglycolic acid side chain at position 2 and thiophene sulfonamide at position 4. An efficient synthetic route to the hydronaphthoquinone sulfonamide scaffold was developed and compound 1 was synthesized in-house to confirm the structure and activity (IC50 = 3.0 +/- 1.6 microM [n=25]). Novel hydronaphthoquinone derivatives of the hit 1 were designed, synthesized and evaluated as proteasome inhibitors. The structure activity relationship (SAR) guided synthesis of more than 170 derivatives revealed that the thioglycolic acid side chain is required and the carboxylic acid group of this side chain is critical to the CT-L inhibitory activity of compound 1. Furthermore, replacement of the carboxylic acid with carboxylic acid isosteres such as tetrazole or triazole greatly improves potency. Compounds with a thio-tetrazole or thio-triazole side chain in position 2, where the thiophene was replaced by hydrophobic aryl moieties were the most active compounds with up to 20-fold greater CT-L inhibitory than compound 1 (compounds 15e, 15f, 15h 15j, IC50 values around 200 nM and compound 29, IC50 = 150 nM). The synthetic iterations described here not only led to improving potency in vitro but also resulted in the identification of compounds that are more active such as 39 (IC50 = 0.44 to 1.01 microM) than 1 (IC50 = 3.54 to 7.22 microM) at inhibiting the proteasome CT-L activity in intact breast cancer cells. Treatment with 39 also resulted in the accumulation of ubiquitinated cellular proteins and inhibition of tumor cell proliferation of breast cancer cells. The hit 1 and its analog 39 inhibited proteasome CT-L activity irreversibly.

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Correction to Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-c]pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone.

Publication Date: 2012 Jan 12 PMID: 22217425
Authors: Vallee, F. - Carrez, C. - Pilorge, F. - Dupuy, A. - Parent, A. - Bertin, L. - Thompson, F. - Ferrari, P. - Fassy, F. - Lamberton, A. - Thomas, A. - Arrebola, R. - Guerif, S. - Rohaut, A. - Certal, V. - Ruxer, J. M. - Gouyon, T. - Delorme, C. - Jouanen, A. - Dumas, J. - Grepin, C. - Combeau, C. - Goulaouic, H. - Dereu, N. - Mikol, V. - Mailliet, P. - Minoux, H.
Journal: J Med Chem

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The Bivalent Ligand Approach Leads to Highly Potent and Selective Acylguanidine-Type Histamine H(2) Receptor Agonists.

Publication Date: 2012 Jan 25 PMID: 22216892
Authors: Birnkammer, T. - Spickenreither, A. - Brunskole, I. - Lopuch, M. - Kagermeier, N. - Bernhardt, G. - Dove, S. - Seifert, R. - Elz, S. - Buschauer, A.
Journal: J Med Chem

Bivalent histamine H(2) receptor (H(2)R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by N(G)-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H(2)R agonism in GTPase and [(35)S]GTPgammaS binding assays at guinea pig (gp) and human (h) H(2)R-Gsalpha(S) fusion proteins including various H(2)R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H(1), H(3), and H(4) receptors. The bivalent ligands are H(2)R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than histamine at the gpH(2)R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H(2)R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH(2) groups) to simultaneously occupy two orthosteric binding sites in H(2)R dimers are nearly inactive, whereas the highest potency resides in compounds with considerably shorter spacers. Thus, there is no evidence for interaction with H(2)R dimers. The high agonistic potency may result from interaction with an accessory binding site at the same receptor protomer.

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Linker-Based Hemisuccinate Derivatives of Artemisinin: Synthesis and Antimalarial Assessment against Multidrug-Resistant Plasmodium yoelii nigeriensis in Mice (1).

Publication Date: 2012 Jan 25 PMID: 22216834
Authors: Singh, C. - Kanchan, R. - Chaudhary, S. - Puri, S. K.
Journal: J Med Chem

Artesunic acid 5, the hemisuccinate derivative of dihydroartemisinin 2, is the only clinically useful water-soluble derivative of artemisinin 1. However, being a lactol ester, it is rapidly hydrolyzed back to dihydroartemisinin in aqueous alkaline solution, a reaction that seriously limits its utility. A new series of potentially more stable linker-based hemisuccinate derivatives 12a-i and 14a-c have been prepared. The process involved acid-catalyzed reaction of dihydroartemisinin with various diols and polyethylene glycols to give hydroxy-functionalized ethers 7a-i and 10a-c and their further derivatization to hemisuccinate esters 12a-i and 14a-c. Both the hydroxy-functionalized ethers 7a-i and 10a-c and their hemisuccinate derivatives 12a-i and 14a-c have been assessed for antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. Several of these hemisuccinate derivatives have shown very promising activity. Hemisuccinate derivatives 12f and 12i, the two most active compounds of the series, provided 100% protection to malaria-infected mice at 24 mg/kg x 4 days and therefore are twice as potent as artesunic acid, which provides a similar level of protection at 48 mg/kg x 4 days.

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The 1.8 A Crystal Structure of ACTIBIND Suggests a Mode of Action for T2 Ribonucleases As Antitumorigenic Agents.

Publication Date: 2012 Jan 31 PMID: 22216760
Authors: de Leeuw, M. - Gonzalez, A. - Lanir, A. - Roiz, L. - Smirnoff, P. - Schwartz, B. - Shoseyov, O. - Almog, O.
Journal: J Med Chem

ACTIBIND and its human homologue RNASET2 are T2 ribonucleases (RNases). RNases are ubiquitous and efficient enzymes that hydrolyze RNA to 3' mononucleotides and also possess antitumorigenic and antiangiogenic activities. Previously, we have shown that ACTIBIND and RNASET2 bind actin and interfere with the cytoskeletal network structure, thereby inhibiting cell motility and invasiveness in cancer and in endothelial cells. We also showed that ACTIBIND binds actin in a molar ratio of 1:2. Here, we further characterize ACTIBIND and determine its crystal structure at 1.8 A resolution, which enables us to propose two structural elements that create binding sites to actin. We suggest that each of these binding sites is composed of one cysteine residue and one conserved amino acid region. These binding sites possibly interfere with the cytoskeleton network structure and as such may be responsible for the antitumorigenic and antiangiogenic activities of ACTIBIND and its human analogue RNASET2.

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Avenues for the Development of Therapeutics That Target Trace Amine Associated Receptor 1 (TAAR1).

Publication Date: 2012 Jan 20 PMID: 22214431
Authors: Miller, G. M.
Journal: J Med Chem

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Structure-Activity Relationships of Cyanoquinolines with Corrector-Potentiator Activity in DeltaF508 Cystic Fibrosis Transmembrane Conductance Regulator Protein.

Publication Date: 2012 Jan 23 PMID: 22214395
Authors: Knapp, J. M. - Wood, A. B. - Phuan, P. W. - Lodewyk, M. W. - Tantillo, D. J. - Verkman, A. S. - Kurth, M. J.
Journal: J Med Chem

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, DeltaF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing DeltaF508-CFTR targeting) and potentiator ("Po", normalizing DeltaF508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search --> force-field lowest energy assessment --> geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct pi-stacking conformations to elicit corrector and potentiator activities.

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Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists.

Publication Date: 2012 Jan 24 PMID: 22214363
Authors: Ibrahim, M. A. - Johnson, H. W. - Jeong, J. W. - Lewis, G. L. - Shi, X. - Noguchi, R. T. - Williams, M. - Leahy, J. W. - Nuss, J. M. - Woolfrey, J. - Banica, M. - Bentzien, F. - Chou, Y. C. - Gibson, A. - Heald, N. - Lamb, P. - Mattheakis, L. - Matthews, D. - Shipway, A. - Wu, X. - Zhang, W. - Zhou, S. - Shankar, G.
Journal: J Med Chem

A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.

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Nonquaternary reactivators for organophosphate-inhibited cholinesterases.

Publication Date: 2012 Jan 12 PMID: 22206546
Authors: Kalisiak, J. - Ralph, E. C. - Cashman, J. R.
Journal: J Med Chem

A new class of amidine-oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) was synthesized and tested in vitro and in vivo. Compared with 2-PAM, the most promising cyclic amidine-oxime (i.e., 12e) showed comparable or greater reactivation of OP-inactivated AChE and OP-inactivated BChE. To the best of our knowledge, this is the first report of a nonquaternary oxime that has, comparable to 2-PAM, in vitro potency for reactivation of Sarin (GB)-inhibited AChE and BChE. Amidine-oximes were tested in vitro, and reactivation rates for OP-inactivated butyrylcholinesterase (BChE) were greater than those for 2-PAM or MINA. Amidine-oxime reactivation rates for OP-inactivated acetylcholinesterase (AChE) were lower compared to 2-PAM but greater compared with MINA. Amidine-oximes were tested in vivo for protection against the toxicity of nerve agent model compounds. (i.e., a model of Sarin). Post-treatment (i.e., 5 min after OP exposure, i.p,) with amidine oximes 7a-c and 12a, 12c, 12e, 12f, and 15b (145 mumol/kg, i.p.) protected 100% of the mice challenged with the sarin model compound. Even at 25% of the initial dose of amidine-oxime (i.e., a dose of 36 mumol/kg, i.p.), 7b and 12e protected 100% of the animals challenged with the sarin nerve agent model compound that caused lethality in 6/11 animals without amidine-oxime.

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Design, synthesis, and biological evaluation of potent quinoline and pyrroloquinoline ammosamide analogues as inhibitors of quinone reductase 2.

Publication Date: 2012 Jan 12 PMID: 22206487
Authors: Reddy, P. V. - Jensen, K. C. - Mesecar, A. D. - Fanwick, P. E. - Cushman, M.
Journal: J Med Chem

A variety of ammosamide B analogues have been synthesized and evaluated as inhibitors of quinone reductase 2 (QR2). The potencies of the resulting series of QR2 inhibitors range from 4.1 to 25,200 nM. The data provide insight into the structural parameters necessary for QR2 inhibitory activity. The natural product ammosamide B proved to be a potent QR2 inhibitor, and the potencies of the analogues generally decreased as their structures became more distinct from that of ammosamide B. Methylation of the 8-amino group of ammosamide B was an exception, resulting in an increase in quinone reductase 2 inhibitory activity from an IC(50) of 61 nM to IC(50) 4.1 nM.

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Drug-to-Genome-to-Drug, Step 2: Reversing Selectivity in a Series of Antiplasmodial Compounds.

Publication Date: 2012 Jan 24 PMID: 22204607
Authors: Beghyn, T. B. - Charton, J. - Leroux, F. - Henninot, A. - Reboule, I. - Cos, P. - Maes, L. - Deprez, B.
Journal: J Med Chem

In a recent paper, we have described the discovery of antimalarial compounds derived from tadalafil, using a drug-to-genome-to-drug approach ( J. Med. Chem. 2011 , 54 ( 9 ), pp 3222 - 3240 ). We have shown that these derivatives inhibit the phosphodiesterase activity of Plasmodium falciparum and the parasite growth in culture. In this paper, we describe the optimization of these compounds. A direct consequence of our approach based on gene orthology is the lack of selectivity of the compounds over the original activity on the human target. We demonstrate here that it is possible to take advantage of subtle differences in SAR between HsPDE5 inhibition and antiplasmodial activity to improve significantly the selectivity. In particular, the replacement of the piperonyl group in compound 2 by a dimethoxyphenyl group was the best way to optimize selectivity. This observation is consistent with the differences between human and plasmodial sequences in the Q2 pocket receiving this group.

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Ruthenium-Arene Complexes of Curcumin: X-Ray and Density Functional Theory Structure, Synthesis, and Spectroscopic Characterization, in Vitro Antitumor Activity, and DNA Docking Studies of (p-Cymene)Ru(curcuminato)chloro.

Publication Date: 2012 Jan 20 PMID: 22204522
Authors: Caruso, F. - Rossi, M. - Benson, A. - Opazo, C. - Freedman, D. - Monti, E. - Gariboldi, M. B. - Shaulky, J. - Marchetti, F. - Pettinari, R. - Pettinari, C.
Journal: J Med Chem

The in vitro antiproliferative activity of the title compound on five tumor cell lines shows preference for the colon-rectal tumor HCT116, IC(50) = 13.98 muM, followed by breast MCF7 (19.58 muM) and ovarian A2780 (23.38 muM) cell lines; human glioblastoma U-87 and lung carcinoma A549 are less sensitive. A commercial curcumin reagent, also containing demethoxy and bis-demethoxy curcumin, was used to synthesize the title compound, and so (p-cymene)Ru(demethoxy-curcuminato)chloro was also isolated and chemically characterized. The crystal structure of the title compound shows (1) the chlorine atom linking two neighboring complexes through H-bonds with two O(hydroxyl), forming an infinite two-step network; (2) significant twist in the curcuminato, 20 degrees between the planes of the two phenyl rings. This was also seen in the docking of the Ru-complex onto a rich guanine B-DNA decamer, where a Ru-N7(guanine) interaction is detected. This Ru-N7(guanine) interaction is also seen with ESI-MS on a Ru-complex-guanosine derivative.

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Correction to Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening.

Publication Date: 2012 Jan 12 PMID: 22204385
Authors: Lack, N. A. - Axerio-Cilies, P. - Tavassoli, P. - Han, F. Q. - Chan, K. H. - Feau, C. - Leblanc, E. - Guns, E. T. - Guy, R. K. - Rennie, P. S. - Cherkasov, A.
Journal: J Med Chem

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Discovery of (S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)n icotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus.

Publication Date: 2012 Jan 24 PMID: 22196621
Authors: Pfefferkorn, J. A. - Guzman-Perez, A. - Litchfield, J. - Aiello, R. - Treadway, J. L. - Pettersen, J. - Minich, M. L. - Filipski, K. J. - Jones, C. S. - Tu, M. - Aspnes, G. - Risley, H. - Bian, J. - Stevens, B. D. - Bourassa, P. - D'Aquila, T. - Baker, L. - Barucci, N. - Robertson, A. S. - Bourbonais, F. - Derksen, D. R. - Macdougall, M. - Cabrera, O. - Chen, J. - Lapworth, A. L. - Landro, J. A. - Zavadoski, W. J. - Atkinson, K. - Haddish-Berhane, N. - Tan, B. - Yao, L. - Kosa, R. E. - Varma, M. V. - Feng, B. - Duignan, D. B. - El-Kattan, A. - Murdande, S. - Liu, S. - Ammirati, M. - Knafels, J. - Dasilva-Jardine, P. - Sweet, L. - Liras, S. - Rolph, T. P.
Journal: J Med Chem

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic beta-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

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Design of Triazole-Stapled BCL9 alpha-Helical Peptides to Target the beta-Catenin/B-Cell CLL/lymphoma 9 (BCL9) Protein-Protein Interaction.

Publication Date: 2012 Jan 24 PMID: 22196480
Authors: Kawamoto, S. A. - Coleska, A. - Ran, X. - Yi, H. - Yang, C. Y. - Wang, S.
Journal: J Med Chem

The interaction between beta-catenin and B-cell CLL/lymphoma 9 (BCL9), critical for the transcriptional activity of beta-catenin, is mediated by a helical segment from BCL9 and a large binding groove in beta-catenin. Design of potent, metabolically stable BCL9 peptides represents an attractive approach to inhibit the activity of beta-catenin. In this study, we report the use of the Huisgen 1,3-dipolar cycloaddition reaction to generate triazole-stapled BCL9 alpha-helical peptides. The high efficiency and mild conditions of this "click" reaction combined with the ease of synthesis of the necessary unnatural amino acids allows for facile synthesis of triazole-stapled peptides. We have performed extensive optimization of this approach and identified the optimal combinations of azido and alkynyl linkers necessary for stapling BCL9 helices. The unsymmetrical nature of the triazole staple also allowed the synthesis of double-stapled BCL9 peptides, which show a marked increase in helical character and an improvement in binding affinity and metabolic stability relative to wild-type and linear BCL9 peptides. This study lays the foundation for further optimization of these triazole-stapled BCL9 peptides as potent, metabolically stable, and cell-permeable inhibitors to target the beta-catenin and BCL9 interaction.

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Chemical modification of the multitarget neuroprotective compound fisetin.

Publication Date: 2012 Jan 12 PMID: 22192055
Authors: Chiruta, C. - Schubert, D. - Dargusch, R. - Maher, P.
Journal: J Med Chem

Many factors are implicated in age-related central nervous system (CNS) disorders, making it unlikely that modulating only a single factor will provide effective treatment. Perhaps a better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Recently, we identified an orally active, neuroprotective, and cognition-enhancing molecule, the flavonoid fisetin, that is effective in several animal models of CNS disorders. Fisetin has direct antioxidant activity and can also increase the intracellular levels of glutathione (GSH), the major endogenous antioxidant. In addition, fisetin has both neurotrophic and anti-inflammatory activity. However, its relatively high EC(50) in cell based assays, low lipophilicity, high topological polar surface area (tPSA), and poor bioavailability suggest that there is room for medicinal chemical improvement. Here we describe a multitiered approach to screening that has allowed us to identify fisetin derivatives with significantly enhanced activity in an in vitro neuroprotection model while at the same time maintaining other key activities.

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Synthesis and Toxicopharmacological Evaluation of m-Hydroxymexiletine, the First Metabolite of Mexiletine More Potent Than the Parent Compound on Voltage-Gated Sodium Channels.

Publication Date: 2012 Jan 31 PMID: 22191686
Authors: Catalano, A. - Desaphy, J. F. - Lentini, G. - Carocci, A. - Di Mola, A. - Bruno, C. - Carbonara, R. - De Palma, A. - Budriesi, R. - Ghelardini, C. - Perrone, M. G. - Colabufo, N. A. - Conte Camerino, D. - Franchini, C.
Journal: J Med Chem

The first synthesis of m-hydroxymexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be approximately 2-fold more potent than the parent mexiletine and to have more favorable toxicological properties than mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of mexiletine (metabolite switch), which has turned out to be tainted with common toxicity.

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Neurosteroid Analogues. 17. Inverted Binding Orientations of Androsterone Enantiomers at the Steroid Potentiation Site on gamma-Aminobutyric Acid Type A Receptors.

Publication Date: 2012 Jan 18 PMID: 22191644
Authors: Krishnan, K. - Manion, B. D. - Taylor, A. - Bracamontes, J. - Steinbach, J. H. - Reichert, D. E. - Evers, A. S. - Zorumski, C. F. - Mennerick, S. - Covey, D. F.
Journal: J Med Chem

The enantiomer pair androsterone and ent-androsterone are positive allosteric modulators of gamma-aminobutyric acid (GABA) type A receptors. Each enantiomer was shown to bind at the same receptor site. Binding orientations of the enantiomers at this site were deduced using enantiomer pairs containing OBn substituents at either C-7 or C-11. 11beta-OBn-substituted steroids and 7alpha-OBn-substituted ent-steroids potently displace [(35)S]-tert-butylbicyclophosphorothionate, augment GABA currents, and anesthetize tadpoles. In contrast, 7beta-OBn-substituted steroids and 11alpha-OBn-substituted ent-steroids have diminished actions. The results suggest that the binding orientations of the active analogues are inverted relative to each other with the 7alpha- and 11beta-substituents similarly located on the edges of the molecules not in contact with the receptor surface. Analogue potentiation of the GABA current was abrogated by an alpha(1) subunit Q241L mutation, indicating that the active analogues act at the same sites in alpha(1)beta(2)gamma(2L) receptors previously associated with positive neurosteroid modulation.

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Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes , T. rubrum , and MDA-MB-231 Cancer Cells.

Publication Date: 2012 Jan 26 PMID: 22191585
Authors: Ronnest, M. H. - Raab, M. S. - Anderhub, S. - Boesen, S. - Kramer, A. - Larsen, T. O. - Clausen, M. H.
Journal: J Med Chem

Griseofulvin and 53 analogues of this compound have been tested against the pathogenic dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes as well as against the breast cancer cell line MDA-MB-231. The modifications to griseofulvin include the 4, 5, 6, 2', 3', and 4' positions. The SAR of the griseofulvin analogues toward the two fungi followed the same trend with the majority being less active than griseofulvin and none had more than twice the potency of the parent compound. A comparison of the antifungal and the anticancer SAR revealed distinct differences, as the majority of analogues showed increased activity against the cancer cell line MDA-MB-231, highlighted by 2'-benzyloxy-2'-demethoxy-griseofulvin, which showed low activity against both fungi but was among the most potent compounds against MDA-MB-231 cancer cells. Tubulin has been proposed as the target of griseofulvin in both fungal and mammalian cells, but the differences revealed by this SAR study strongly suggest that the mode-of-action of the compound class toward fungi and mammalian cancer cells is different.

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Wnt inhibition correlates with human embryonic stem cell cardiomyogenesis: a structure-activity relationship study based on inhibitors for the wnt response.

Publication Date: 2012 Jan 26 PMID: 22191557
Authors: Lanier, M. - Schade, D. - Willems, E. - Tsuda, M. - Spiering, S. - Kalisiak, J. - Mercola, M. - Cashman, J. R.
Journal: J Med Chem

Human embryonic stem cell-based high-content screening of 550 known signal transduction modulators showed that one "lead" (1, a recently described inhibitor of the proteolytic degradation of Axin) stimulated cardiomyogenesis. Because Axin controls canonical Wnt signaling, we conducted an investigation to determine whether the cardiogenic activity of 1 is Wnt-dependent, and we developed a structure-activity relationship to optimize the cardiogenic properties of 1. We prepared analogues with a range of potencies (low nanomolar to inactive) for Wnt/beta-catenin inhibition and for cardiogenic induction. Both functional activities correlated positively (r(2) = 0.72). The optimal compounds induced cardiogenesis 1.5-fold greater than 1 at 30-fold lower concentrations. In contrast, no correlation was observed for cardiogenesis and modulation of transforming growth factor beta (TGFbeta)/Smad signaling that prominently influences cardiogenesis. Taken together, these data show that Wnt signaling inhibition is essential for cardiogenic activity and that the pathway can be targeted for the design of druglike cardiogenic molecules.

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Transition in leadership: opportunities and challenges.

Publication Date: 2012 Jan 12 PMID: 22191537
Authors: Wang, S. - Georg, G. I.
Journal: J Med Chem

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ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis.

Publication Date: 2012 Jan 12 PMID: 22191331
Authors: Chen, T. - Benmohamed, R. - Kim, J. - Smith, K. - Amante, D. - Morimoto, R. I. - Kirsch, D. R. - Ferrante, R. J. - Silverman, R. B.
Journal: J Med Chem

Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. The arylsulfanyl pyrazolone (ASP) scaffold was one of the active scaffolds identified in a cell-based high throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD1) induced toxicity and aggregation as a marker for ALS. The initial ASP hit compounds were potent and had favorable ADME properties but had poor microsomal and plasma stability. Here, we identify the microsomal metabolite and describe synthesized analogues of these ASP compounds to address the rapid metabolism. Both in vitro potency and pharmacological properties of the ASP scaffold have been dramatically improved via chemical modification to the corresponding sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro pharmacokinetic properties, was tested in vivo for its pharmacokinetic profile, brain penetration, and efficacy in an ALS mouse model. The analogue showed sustained blood and brain levels in vivo and significant activity in the mouse model of ALS, thus validating the new aryloxanyl pyrazolone scaffold as an important novel therapeutic lead for the treatment of this neurodegenerative disorder.

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Oxadiazoles in Medicinal Chemistry.

Publication Date: 2012 Jan 13 PMID: 22185670
Authors: Bostrom, J. - Hogner, A. - Llinas, A. - Wellner, E. - Plowright, A. T.
Journal: J Med Chem

Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and amide functionalities. The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole matched pairs in the AstraZeneca compound collection. In virtually all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude lower lipophilicity (log D), as compared to its isomeric partner. Significant differences are also observed with respect to metabolic stability, hERG inhibition, and aqueous solubil ity, favoring the 1,3,4-oxadiazole isomers. The difference in profile between the 1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically different charge distributions (e.g., dipole moments). To facilitate the use of these heteroaromatic rings, novel synthetic routes for ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild conditions, are described.

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Tailoring of integrin ligands: probing the charge capability of the metal ion-dependent adhesion site.

Publication Date: 2012 Jan 26 PMID: 22185640
Authors: Bollinger, M. - Manzenrieder, F. - Kolb, R. - Bochen, A. - Neubauer, S. - Marinelli, L. - Limongelli, V. - Novellino, E. - Moessmer, G. - Pell, R. - Lindner, W. - Fanous, J. - Hoffman, A. - Kessler, H.
Journal: J Med Chem

Intervention in integrin-mediated cell adhesion and integrin signaling pathways is an ongoing area of research in medicinal chemistry and drug development. One key element in integrin-ligand interaction is the coordination of the bivalent cation at the metal ion-dependent adhesion site (MIDAS) by a carboxylic acid function, a consistent feature of all integrin ligands. With the exception of the recently discovered hydroxamic acids, all bioisosteric attempts to replace the carboxylic acid of integrin ligands failed. We report that phosphinates as well as monomethyl phosphonates represent excellent isosters, when introduced into integrin antagonists for the platelet integrin alphaIIbbeta3. The novel inhibitors exhibit in vitro and ex vivo activities in the low nanomolar range. Steric and charge requirements of the MIDAS region were unraveled, thus paving the way for an in silico prediction of ligand activity and in turn the rational design of the next generation of integrin antagonists.

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Huprine-Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer's and Prion Diseases.

Publication Date: 2012 Jan 26 PMID: 22185619
Authors: Galdeano, C. - Viayna, E. - Sola, I. - Formosa, X. - Camps, P. - Badia, A. - Clos, M. V. - Relat, J. - Ratia, M. - Bartolini, M. - Mancini, F. - Andrisano, V. - Salmona, M. - Minguillon, C. - Gonzalez-Munoz, G. C. - Rodriguez-Franco, M. I. - Bidon-Chanal, A. - Luque, F. J. - Munoz-Torrero, D.
Journal: J Med Chem

A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the beta-amyloid peptide (Abeta) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Abeta aggregation, and beta-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.

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Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase.

Publication Date: 2012 Jan 23 PMID: 22185586
Authors: Sofia, M. J. - Chang, W. - Furman, P. A. - Mosley, R. T. - Ross, B. S.
Journal: J Med Chem

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Structure-activity relationship of a new series of reversible dual monoacylglycerol lipase/fatty Acid amide hydrolase inhibitors.

Publication Date: 2012 Jan 26 PMID: 22185522
Authors: Cisneros, J. A. - Bjorklund, E. - Gonzalez-Gil, I. - Hu, Y. - Canales, A. - Medrano, F. J. - Romero, A. - Ortega-Gutierrez, S. - Fowler, C. J. - Lopez-Rodriguez, M. L.
Journal: J Med Chem

The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play independent and nonredundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (+/-)-oxiran-2-ylmethyl 6-(1,1'-biphenyl-4-yl)hexanoate (8) and (2R)-(-)-oxiran-2-ylmethyl(4-benzylphenyl)acetate (30) stand out as potent inhibitors of human recombinant MAGL (IC(50) (8) = 4.1 muM; IC(50) (30) = 2.4 muM), rat brain monoacylglycerol hydrolysis (IC(50) (8) = 1.8 muM; IC(50) (30) = 0.68 muM), and rat brain FAAH (IC(50) (8) = 5.1 muM; IC(50) (30) = 0.29 muM). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (8) or noncompetitive nature (30). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors.

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Synthesis and Structure-Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure.

Publication Date: 2012 Jan 20 PMID: 22185476
Authors: Yamazaki, Y. - Tanaka, K. - Nicholson, B. - Deyanat-Yazdi, G. - Potts, B. - Yoshida, T. - Oda, A. - Kitagawa, T. - Orikasa, S. - Kiso, Y. - Yasui, H. - Akamatsu, M. - Chinen, T. - Usui, T. - Shinozaki, Y. - Yakushiji, F. - Miller, B. R. - Neuteboom, S. - Palladino, M. - Kanoh, K. - Lloyd, G. K. - Hayashi, Y.
Journal: J Med Chem

Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.

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Aminoferrocene-based prodrugs activated by reactive oxygen species.

Publication Date: 2012 Jan 26 PMID: 22185340
Authors: Hagen, H. - Marzenell, P. - Jentzsch, E. - Wenz, F. - Veldwijk, M. R. - Mokhir, A.
Journal: J Med Chem

Cancer cells generally generate higher amounts of reactive oxygen species than normal cells. On the basis of this difference, prodrugs have been developed (e.g., hydroxyferrocifen), which remain inactive in normal cells, but become activated in cancer cells. In this work we describe novel aminoferrocene-based prodrugs, which, in contrast to hydroxyferrocifen, after activation form not only quinone methides (QMs), but also catalysts (iron or ferrocenium ions). The released products act in a concerted fashion. In particular, QMs alkylate glutathione, thereby inhibiting the antioxidative system of the cell, whereas the iron species induce catalytic generation of hydroxyl radicals. Since the catalysts are formed as products of the activation reaction, it proceeds autocatalytically. The most potent prodrug described here is toxic toward cancer cells (human promyelocytic leukemia (HL-60), IC(50) = 9 muM, and human glioblastoma-astrocytoma (U373), IC(50) = 25 muM), but not toxic (up to 100 muM) toward representative nonmalignant cells (fibroblasts).

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Tri- and tetrasubstituted pyrazole derivates: regioisomerism switches activity from p38MAP kinase to important cancer kinases.

Publication Date: 2012 Jan 26 PMID: 22185282
Authors: Thaher, B. A. - Arnsmann, M. - Totzke, F. - Ehlert, J. E. - Kubbutat, M. H. - Schachtele, C. - Zimmermann, M. O. - Koch, P. - Boeckler, F. M. - Laufer, S. A.
Journal: J Med Chem

In the course of searching for new p38alpha MAP kinase inhibitors, we found that the regioisomeric switch from 3-(4-fluorophenyl)-4-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine to 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine led to an almost complete loss of p38alpha inhibition, but they showed activity against important cancer kinases. Among the tested derivatives, 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazol-5 -amine (6a) exhibited the best activity, with IC(50) in the nanomolar range against Src, B-Raf wt, B-Raf V600E, EGFRs, and VEGFR-2, making it a good lead for novel anticancer programs.

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Peroxisome Proliferator-Activated Receptors (PPARs) Have Multiple Binding Points That Accommodate Ligands in Various Conformations: Phenylpropanoic Acid-Type PPAR Ligands Bind to PPAR in Different Conformations, Depending on the Subtype.

Publication Date: 2012 Jan 26 PMID: 22185225
Authors: Kuwabara, N. - Oyama, T. - Tomioka, D. - Ohashi, M. - Yanagisawa, J. - Shimizu, T. - Miyachi, H.
Journal: J Med Chem

Human peroxisome proliferator-activated receptors (hPPARs) are ligand-dependent transcription factors that control various biological responses, and there are three subtypes: hPPARalpha, hPPARdelta, and hPPARgamma. We report here that alpha-substituted phenylpropanoic acid-type hPPAR agonists with similar structure bind to the hPPAR ligand binding domain (LBD) in different conformations, depending on the receptor subtype. These results might indicate that hPPAR ligand binding pockets have multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands.

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Latent Hit Series Hidden in High-Throughput Screening Data.

Publication Date: 2012 Jan 23 PMID: 22185196
Authors: Varin, T. - Didiot, M. C. - Parker, C. N. - Schuffenhauer, A.
Journal: J Med Chem

Recently a novel method termed compound set enrichment (CSE) has been described that uses the activity distribution of a structural class of compounds to identify hit series from primary screening data. This report describes how this method can be used to identify such hit series, even when no hits according to conventional hit-calling methods for a given structural class are present in the data set. Such series, which were called latent hit series, were identified prospectively in a cell-based screening campaign and also in a series of retrospective analyses of publicly available data sets from PubChem. The assay used for the prospective case study was developed to identify compounds modulating protein translation directed from the internal ribosome entry site (IRES) of the encephalomyocarditis virus (EMCV) genomic RNA. The assay was designed with the ability to detect two assay readouts. The first assay readout monitors compound effects on IRES-directed translation, and the second readout monitors the cell viability and general effect on protein expression. By applying CSE separately to both of them, six validated latent hit series with apparently no effects on cell viability were identified. For each of these series, further testing of new compounds enabled identification of additional hits, also apparently with no effect on cell viability. These validated latent hit series would have been missed by a conventional cutoff-based hit-calling approach. This prospective study further supports CSE as a method for the analysis of high-throughput screening experiments.

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Potent Inhibitors of LpxC for the Treatment of Gram-Negative Infections.

Publication Date: 2012 Jan 26 PMID: 22175825
Authors: Brown, M. F. - Reilly, U. - Abramite, J. A. - Arcari, J. T. - Oliver, R. - Barham, R. A. - Che, Y. - Chen, J. M. - Collantes, E. M. - Chung, S. W. - Desbonnet, C. - Doty, J. - Doroski, M. - Engtrakul, J. J. - Harris, T. M. - Huband, M. - Knafels, J. D. - Leach, K. L. - Liu, S. - Marfat, A. - Marra, A. - McElroy, E. - Melnick, M. - Menard, C. A. - Montgomery, J. I. - Mullins, L. - Noe, M. C. - O'Donnell, J. - Penzien, J. - Plummer, M. S. - Price, L. M. - Shanmugasundaram, V. - Thoma, C. - Uccello, D. P. - Warmus, J. S. - Wishka, D. G.
Journal: J Med Chem

In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid 1a.

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Discovery and Evaluation of a Non-Zn Chelating, Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitor for Potential Intra-articular Treatment of Osteoarthritis.

Publication Date: 2012 Jan 26 PMID: 22175799
Authors: Gege, C. - Bao, B. - Bluhm, H. - Boer, J. - Gallagher, B. M. - Korniski, B. - Powers, T. S. - Steeneck, C. - Taveras, A. G. - Baragi, V. M.
Journal: J Med Chem

Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carb amoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.

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Discovery of cis-N-(1-(4-(Methylamino)cyclohexyl)indolin-6-yl)thiophene-2-carboximidami de: A 1,6-Disubstituted Indoline Derivative as a Highly Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) without Any Cardiovascular Liabilities.

Publication Date: 2012 Jan 26 PMID: 22175766
Authors: Annedi, S. C. - Ramnauth, J. - Maddaford, S. P. - Renton, P. - Rakhit, S. - Mladenova, G. - Dove, P. - Silverman, S. - Andrews, J. S. - Felice, M. D. - Porreca, F.
Journal: J Med Chem

A series of 1,6-disubstituted indoline derivatives were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS) designed to mitigate the cardiovascular liabilities associated with previously reported tetrahydroquinoline-based selective neuronal NOS inhibitors due to higher lipophilicity ( J. Med. Chem. 2011 , 54 , 5562 - 5575 ). This new series produced similar potency and selectivity among the NOS isoforms and was devoid of any cardiovascular liabilities associated with QT prolongation due to hERG activity or endothelial NOS mediated vasoconstriction effect. The SAR studies led to the identification of cis-45, which was shown to reverse thermal hyperalgesia in vivo in the spinal nerve ligation model of neuropathic pain with excellent safety profile (off-target activities at 80 CNS related receptors/ion channels/transporters). The results presented in this report make cis-45 as an ideal tool for evaluating the potential role of selective nNOS inhibitors in CNS related disorders where excess NO produced by nNOS is thought to play a crucial role.

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Antiandrogenic, Maspin Induction, and Antiprostate Cancer Activities of Tanshinone IIA and Its Novel Derivatives with Modification in Ring A.

Publication Date: 2012 Jan 26 PMID: 22175694
Authors: Liu, W. - Zhou, J. - Geng, G. - Shi, Q. - Sauriol, F. - Wu, J. H.
Journal: J Med Chem

Expression of metastatic suppressor maspin is lost in advanced prostate cancer. Clinically relevant mutations in androgen receptor (AR) convert antiandrogens into AR agonists, promoting prostate tumor growth. We discovered tanshinone IIA (TS-IIA) is a potent antagonist of mutated ARs and induces maspin expression through AR. TS-IIA suppressed AR expression and induced apoptosis in LNCaP cells. Syntheses of TS-IIA derivatives (1-9) revealed that the 4,4-dimethyl group at ring A is important for TS-IIA's antiandrogenic and maspin induction activities.

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Design, Synthesis, and Anaplastic Lymphoma Kinase (ALK) Inhibitory Activity for a Novel Series of 2,4,8,22-Tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9 (21),10,12,16,18-nonaene Macrocycles.

Publication Date: 2012 Jan 12 PMID: 22172029
Authors: Breslin, H. J. - Lane, B. M. - Ott, G. R. - Ghose, A. K. - Angeles, T. S. - Albom, M. S. - Cheng, M. - Wan, W. - Haltiwanger, R. C. - Wells-Knecht, K. J. - Dorsey, B. D.
Journal: J Med Chem

A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9 (21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC(50) = 0.5 nM) and cellular (IC(50) = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.

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Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective alpha4beta2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile.

Publication Date: 2012 Jan 26 PMID: 22171543
Authors: Zhang, H. - Tuckmantel, W. - Eaton, J. B. - Yuen, P. W. - Yu, L. F. - Bajjuri, K. M. - Fedolak, A. - Wang, D. - Ghavami, A. - Caldarone, B. - Paterson, N. E. - Lowe, D. A. - Brunner, D. - Lukas, R. J. - Kozikowski, A. P.
Journal: J Med Chem

Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing alpha4beta2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at alpha4beta2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other alpha4beta2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.

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Discovery of Inhibitors of Soluble Epoxide Hydrolase: A Target with Multiple Potential Therapeutic Indications.

Publication Date: 2012 Jan 17 PMID: 22168898
Authors: Shen, H. C. - Hammock, B. D.
Journal: J Med Chem

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Structural Basis for the Interaction between Casein Kinase 1 Delta and a Potent and Selective Inhibitor.

Publication Date: 2012 Jan 26 PMID: 22168824
Authors: Long, A. - Zhao, H. - Huang, X.
Journal: J Med Chem

Casein kinase 1 delta (CK1delta) and its closest homologue CK1epsilon are key regulators of diverse cellular growth and survival processes such as Wnt signaling, DNA repair, and circadian rhythms. We report three crystal structures of the kinase domain of human CK1delta, one apo and two complexed with a potent and selective CK1delta/epsilon inhibitor PF670462 in two different crystal forms. These structures provide a molecular basis for the strong and specific inhibitor interactions and suggest clues for further development of CK1delta/epsilon inhibitors.

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Discovery and synthesis of namalide reveals a new anabaenopeptin scaffold and peptidase inhibitor.

Publication Date: 2012 Jan 26 PMID: 22168797
Authors: Cheruku, P. - Plaza, A. - Lauro, G. - Keffer, J. - Lloyd, J. R. - Bifulco, G. - Bewley, C. A.
Journal: J Med Chem

The discovery, structure elucidation, and solid-phase synthesis of namalide, a marine natural product, are described. Namalide is a cyclic tetrapeptide; its macrocycle is formed by only three amino acids, with an exocyclic ureido phenylalanine moiety at its C-terminus. The absolute configuration of namalide was established, and analogs were generated through Fmoc-based solid phase peptide synthesis. We found that only natural namalide and not its analogs containing l-Lys or l-allo-Ile inhibited carboxypeptidase A at submicromolar concentrations. In parallel, an inverse virtual screening approach aimed at identifying protein targets of namalide selected carboxypeptidase A as the third highest scoring hit. Namalide represents a new anabaenopeptin-type scaffold, and its protease inhibitory activity demonstrates that the 13-membered macrolactam can exhibit similar activity as the more common hexapeptides.

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The 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances: (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a GABA Aminotransferase Inactivator and New Treatment for Drug Addiction and Infantile Spasms (dagger).

Publication Date: 2012 Jan 26 PMID: 22168767
Authors: Silverman, R. B.
Journal: J Med Chem

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Identification of 1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-meth ylpropan-2-yl)isoxazol-3-yl)urea Hydrochloride (CEP-32496), a Highly Potent and Orally Efficacious Inhibitor of V-RAF Murine Sarcoma Viral Oncogene Homologue B1 (BRAF) V600E.

Publication Date: 2012 Jan 23 PMID: 22168626
Authors: Rowbottom, M. W. - Faraoni, R. - Chao, Q. - Campbell, B. T. - Lai, A. G. - Setti, E. - Ezawa, M. - Sprankle, K. G. - Abraham, S. - Tran, L. - Struss, B. - Gibney, M. - Armstrong, R. C. - Gunawardane, R. N. - Nepomuceno, R. R. - Valenta, I. - Hua, H. - Gardner, M. F. - Cramer, M. D. - Gitnick, D. - Insko, D. E. - Apuy, J. L. - Jones-Bolin, S. - Ghose, A. K. - Herbertz, T. - Ator, M. A. - Dorsey, B. D. - Ruggeri, B. - Williams, M. - Bhagwat, S. - James, J. - Holladay, M. W.
Journal: J Med Chem

The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.

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Correction to Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H(3) Receptor Antagonists with Improved Potency.

Publication Date: 2012 Jan 12 PMID: 22168553
Authors: Sun, M. - Zhao, C. - Gfesser, G. A. - Thiffault, C. - Miller, T. R. - Marsh, K. - Wetter, J. - Curtis, M. - Faghih, R. - Esbenshade, T. A. - Hancock, A. A. - Cowart, M.
Journal: J Med Chem

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Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of foxp3+ T-regulatory cells.

Publication Date: 2012 Jan 26 PMID: 22165909
Authors: Kalin, J. H. - Butler, K. V. - Akimova, T. - Hancock, W. W. - Kozikowski, A. P.
Journal: J Med Chem

Second-generation Tubastatin A analogues were synthesized and evaluated for their ability to inhibit selectively histone deacetylase 6 (HDAC6). Substitutions to the carboline cap group were well-tolerated with substitution at the 2-position of both beta- and gamma-carbolines being optimal for HDAC6 activity and selectivity. Some compounds in this series were determined to have subnanomolar activity at HDAC6 with more than 7000 fold selectivity for HDAC6 versus HDAC1. Selected compounds were then evaluated for their ability to augment the immunosuppressive effect of Foxp3+ regulatory T cells. All compounds tested were found to enhance the ability of regulatory T cells to inhibit the mitotic division of effector T cells both in vitro and in vivo, suggesting that further investigation into the use of these compounds for the treatment of autoimmune disorders is warranted.

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Substituted chromones as highly potent nontoxic inhibitors, specific for the breast cancer resistance protein.

Publication Date: 2012 Jan 26 PMID: 22165858
Authors: Valdameri, G. - Genoux-Bastide, E. - Peres, B. - Gauthier, C. - Guitton, J. - Terreux, R. - Winnischofer, S. M. - Rocha, M. E. - Boumendjel, A. - Di Pietro, A.
Journal: J Med Chem

A series of 13 disubstituted chromones was synthesized. Two types of substituents, on each side of the scaffold, contributed to both the potency of ABCG2 inhibition and the cytotoxicity. The best compound, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4 -one (6g), displayed high-affinity inhibition and low cytotoxicity, giving a markedly high therapeutic index. The chromone derivative specifically inhibited ABCG2 versus other multidrug ABC transporters and was not transported. It constitutes a highly promising candidate for in vivo chemosensitization of ABCG2-expressing tumors.

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Fragment based drug discovery: practical implementation based on (19)f NMR spectroscopy.

Publication Date: 2012 Jan 26 PMID: 22165820
Authors: Jordan, J. B. - Poppe, L. - Xia, X. - Cheng, A. C. - Sun, Y. - Michelsen, K. - Eastwood, H. - Schnier, P. D. - Nixey, T. - Zhong, W.
Journal: J Med Chem

Fragment based drug discovery (FBDD) is a widely used tool for discovering novel therapeutics. NMR is a powerful means for implementing FBDD, and several approaches have been proposed utilizing (1)H-(15)N heteronuclear single quantum coherence (HSQC) as well as one-dimensional (1)H and (19)F NMR to screen compound mixtures against a target of interest. While proton-based NMR methods of fragment screening (FBS) have been well documented and are widely used, the use of (19)F detection in FBS has been only recently introduced (Vulpetti et al. J. Am. Chem. Soc.2009, 131 (36), 12949-12959) with the aim of targeting "fluorophilic" sites in proteins. Here, we demonstrate a more general use of (19)F NMR-based fragment screening in several areas: as a key tool for rapid and sensitive detection of fragment hits, as a method for the rapid development of structure-activity relationship (SAR) on the hit-to-lead path using in-house libraries and/or commercially available compounds, and as a quick and efficient means of assessing target druggability.

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Structure-Activity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase.

Publication Date: 2012 Jan 26 PMID: 22148957
Authors: Chen, K. X. - Vibulbhan, B. - Yang, W. - Sannigrahi, M. - Velazquez, F. - Chan, T. Y. - Venkatraman, S. - Anilkumar, G. N. - Zeng, Q. - Bennet, F. - Jiang, Y. - Lesburg, C. A. - Duca, J. - Pinto, P. - Gavalas, S. - Huang, Y. - Wu, W. - Selyutin, O. - Agrawal, S. - Feld, B. - Huang, H. C. - Li, C. - Cheng, K. C. - Shih, N. Y. - Kozlowski, J. A. - Rosenblum, S. B. - Njoroge, F. G.
Journal: J Med Chem

Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 muM) and cell-based replicon (EC(50) = 0.02 muM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 muM.h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.

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Synthesis and Biological Profile of the pan-Vascular Endothelial Growth Factor Receptor/Tyrosine Kinase with Immunoglobulin and Epidermal Growth Factor-Like Homology Domains 2 (VEGF-R/TIE-2) Inhibitor 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-inda zolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): A Novel Oncology Therapeutic Agent.

Publication Date: 2012 Jan 26 PMID: 22148921
Authors: Hudkins, R. L. - Becknell, N. C. - Zulli, A. L. - Underiner, T. L. - Angeles, T. S. - Aimone, L. D. - Albom, M. S. - Chang, H. - Miknyoczki, S. J. - Hunter, K. - Jones-Bolin, S. - Zhao, H. - Bacon, E. R. - Mallamo, J. P. - Ator, M. A. - Ruggeri, B. A.
Journal: J Med Chem

A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-inda zolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.

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Antimalarial Activity of 9a-N Substituted 15-Membered Azalides with Improved in Vitro and in Vivo Activity over Azithromycin.

Publication Date: 2012 Jan 25 PMID: 22148880
Authors: Peric, M. - Fajdetic, A. - Rupcic, R. - Alihodzic, S. - Ziher, D. - Bukvic Krajacic, M. - Smith, K. S. - Ivezic-Schonfeld, Z. - Padovan, J. - Landek, G. - Jelic, D. - Hutinec, A. - Mesic, M. - Ager, A. - Ellis, W. Y. - Milhous, W. K. - Ohrt, C. - Spaventi, R.
Journal: J Med Chem

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis.

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Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)xanthines as Potent and Selective A(2B) Adenosine Receptor Antagonists.

Publication Date: 2012 Jan 26 PMID: 22148859
Authors: Baraldi, P. G. - Baraldi, S. - Saponaro, G. - Preti, D. - Romagnoli, R. - Piccagli, L. - Cavalli, A. - Recanatini, M. - Moorman, A. R. - Zaid, A. N. - Varani, K. - Borea, P. A. - Tabrizi, M. A.
Journal: J Med Chem

Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A(2B) adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A(2B) adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A(2B)AR, a new series of compounds was synthesized and evaluated in binding studies against the human A(1), A(2A), A(3), and A(2B)ARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A(2B) receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1 H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: K(i) A(2B) = 9.4 nM, IC(50) hA(2B) = 26 nM hA(1)/hA(2B) = 269, hA(2A)/hA(2B) > 106, hA(3)/hA(2B) >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A(2B)AR with good selectivity over AR subtypes (K(i) = 4.0 nM, IC(50) hA(2B) = 20 nM hA(1)/hA(2B) = 183, hA(2A),hA(3)/hA(2B) > 250).

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Automated protein-ligand interaction screening by mass spectrometry.

Publication Date: 2012 Jan 26 PMID: 22148839
Authors: Maple, H. J. - Garlish, R. A. - Rigau-Roca, L. - Porter, J. - Whitcombe, I. - Prosser, C. E. - Kennedy, J. - Henry, A. J. - Taylor, R. J. - Crump, M. P. - Crosby, J.
Journal: J Med Chem

Identifying protein-ligand binding interactions is a key step during early-stage drug discovery. Existing screening techniques are often associated with drawbacks such as low throughput, high sample consumption, and dynamic range limitations. The increasing use of fragment-based drug discovery (FBDD) demands that these techniques also detect very weak interactions (mM K(D) values). This paper presents the development and validation of a fully automated screen by mass spectrometry, capable of detecting fragment binding into the millimolar K(D) range. Low sample consumption, high throughput, and wide dynamic range make this a highly attractive, orthogonal approach. The method was applied to screen 157 compounds in 6 h against the anti-apoptotic protein target Bcl-x(L). Mass spectrometry results were validated using STD-NMR, HSQC-NMR, and ITC experiments. Agreement between techniques suggests that mass spectrometry offers a powerful, complementary approach for screening.

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Bivalent Smac Mimetics with a Diazabicyclic Core as Highly Potent Antagonists of XIAP and cIAP1/2 and Novel Anticancer Agents.

Publication Date: 2012 Jan 12 PMID: 22148838
Authors: Peng, Y. - Sun, H. - Lu, J. - Liu, L. - Cai, Q. - Shen, R. - Yang, C. Y. - Yi, H. - Wang, S.
Journal: J Med Chem

Nonpeptidic, bivalent Smac mimetics designed based upon monovalent Smac mimetics with a diazabicyclic core structure bind to XIAP, cIAP1, and cIAP2 with low to subnanomolar affinities and are highly effective in antagonizing XIAP in cell-free functional assays. They efficiently induce the degradation of cIAP1 and cIAP2 in cancer cells at concentrations as low as 1 nM, activate caspase-3 and -8, and cleave PARP at 3-10 nM. The most potent compounds in the series have IC(50) of 3-5 nM in inhibition of cell growth in both MDA-MB-231and SK-OV-3 cell lines and are promising lead compounds for the development of a new class of cancer therapy.

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Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.

Publication Date: 2012 Jan 12 PMID: 22148754
Authors: Brand, S. - Cleghorn, L. A. - McElroy, S. P. - Robinson, D. A. - Smith, V. C. - Hallyburton, I. - Harrison, J. R. - Norcross, N. R. - Spinks, D. - Bayliss, T. - Norval, S. - Stojanovski, L. - Torrie, L. S. - Frearson, J. A. - Brenk, R. - Fairlamb, A. H. - Ferguson, M. A. - Read, K. D. - Wyatt, P. G. - Gilbert, I. H.
Journal: J Med Chem

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

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Allosteric Modulation of Seven Transmembrane Spanning Receptors: Theory, Practice, and Opportunities for Central Nervous System Drug Discovery.

Publication Date: 2012 Jan 6 PMID: 22148748
Authors: Melancon, B. J. - Hopkins, C. R. - Wood, M. R. - Emmitte, K. A. - Niswender, C. M. - Christopoulos, A. - Conn, P. J. - Lindsley, C. W.
Journal: J Med Chem

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Small Molecule STAT5-SH2 Domain Inhibitors Exhibit Potent Antileukemia Activity.

Publication Date: 2012 Jan 13 PMID: 22148584
Authors: Page, B. D. - Khoury, H. - Laister, R. C. - Fletcher, S. - Vellozo, M. - Manzoli, A. - Yue, P. - Turkson, J. - Minden, M. D. - Gunning, P. T.
Journal: J Med Chem

A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) protein, a key member of the STAT family of signaling proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, Stat5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors ( approximately 150) against STAT5, as well as against STAT3 and STAT1 proteins for SH2 domain selectivity. We herein report the identification of several potent (K(i) < 5 muM) and STAT5 selective (>3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosis (IC(50)'s approximately 20 muM) which correlated with potent and selective suppression of STAT5 phosphorylation, as well as inhibition of STAT5 target genes cyclin D1, cyclin D2, C-MYC, and MCL-1. Moreover, lead agent BP-1-108 showed negligible cytotoxic effects in normal bone marrow cells not expressing activated STAT5 protein. Inhibitors identified in this study represent some of the most potent direct small molecule, nonphosphorylated inhibitors of STAT5 to date.

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Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy.

Publication Date: 2012 Jan 26 PMID: 22148555
Authors: Clark, R. B. - Hunt, D. K. - He, M. - Achorn, C. - Chen, C. L. - Deng, Y. - Fyfe, C. - Grossman, T. H. - Hogan, P. C. - O'Brien, W. J. - Plamondon, L. - Ronn, M. - Sutcliffe, J. A. - Zhu, Z. - Xiao, X. Y.
Journal: J Med Chem

Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of the fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome both efflux (tet(K), tet(A)) and ribosomal protection (tet(M)) tetracycline-resistance mechanisms and are active against Gram-positive and Gram-negative organisms. A murine systemic infection model was used as an oral efficacy screen to rapidly identify compounds with oral bioavailability. Two compounds were identified that exhibit both oral bioavailability in rat and clinically relevant bacterial susceptibility profiles against major respiratory pathogens. One compound demonstrated oral efficacy in rodent lung infection models that was comparable to marketed antibacterial agents.

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Fluorocyclines. 1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: A Potent, Broad Spectrum Antibacterial Agent.

Publication Date: 2012 Jan 26 PMID: 22148514
Authors: Xiao, X. Y. - Hunt, D. K. - Zhou, J. - Clark, R. B. - Dunwoody, N. - Fyfe, C. - Grossman, T. H. - O'Brien, W. J. - Plamondon, L. - Ronn, M. - Sun, C. - Zhang, W. Y. - Sutcliffe, J. A.
Journal: J Med Chem

This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

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A force field with discrete displaceable waters and desolvation entropy for hydrated ligand docking.

Publication Date: 2012 Jan 26 PMID: 22148468
Authors: Forli, S. - Olson, A. J.
Journal: J Med Chem

In modeling ligand-protein interactions, the representation and role of water are of great importance. We introduce a force field and hydration docking method that enables the automated prediction of waters mediating the binding of ligands with target proteins. The method presumes no prior knowledge of the apo or holo protein hydration state and is potentially useful in the process of structure-based drug discovery. The hydration force field accounts for the entropic and enthalpic contributions of discrete waters to ligand binding, improving energy estimation accuracy and docking performance. The force field has been calibrated and validated on a total of 417 complexes (197 training set; 220 test set), then tested in cross-docking experiments, for a total of 1649 ligand-protein complexes evaluated. The method is computationally efficient and was used to model up to 35 waters during docking. The method was implemented and tested using unaltered AutoDock4 with new force field tables.

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Niphatenones, Glycerol Ethers from the Sponge Niphates digitalis Block Androgen Receptor Transcriptional Activity in Prostate Cancer Cells: Structure Elucidation, Synthesis, and Biological Activity.

Publication Date: 2012 Jan 12 PMID: 22148427
Authors: Meimetis, L. G. - Williams, D. E. - Mawji, N. R. - Banuelos, C. A. - Lal, A. A. - Park, J. J. - Tien, A. H. - Fernandez, J. G. - de Voogd, N. J. - Sadar, M. D. - Andersen, R. J.
Journal: J Med Chem

Extracts of the marine sponge Niphates digitalis collected in Dominica showed strong activity in a cell-based assay designed to detect antagonists of the androgen receptor (AR) that could act as lead compounds for the development of a new class of drugs to treat castration recurrent prostate cancer (CRPC). Assay-guided fractionation showed that niphatenones A (3) and B (4), two new glycerol ether lipids, were the active components of the extracts. The structures of 3 and 4 were elucidated by analysis of NMR and MS data and confimed via total synthesis. Biological evaluation of synthetic analogues of the niphatenones has shown that the enantiomers 7 and 8 are more potent than the natural products in the screening assay and defined preliminary SAR for the new AR antagonist pharmacophore, including the finding that the Michael acceptor enone functionality is not required for activity. Niphatenone B (4) and its enantiomer 8 blocked androgen-induced proliferation of LNCaP prostate cancer cells but had no effect on the proliferation of PC3 prostate cancer cells that do not express functional AR, consistent with activity as AR antagonists. Use of the propargyl ether 44 and Click chemistry showed that niphatenone B binds covalently to the activation function-1 (AF1) region of the AR N-terminus domain (NTD).

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Structure-Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2, 1-b][1,3]oxazine (PA-824).

Publication Date: 2012 Jan 12 PMID: 22148391
Authors: Blaser, A. - Palmer, B. D. - Sutherland, H. S. - Kmentova, I. - Franzblau, S. G. - Wan, B. - Wang, Y. - Ma, Z. - Thompson, A. M. - Denny, W. A.
Journal: J Med Chem

Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2, 1-b][1,3]oxazine (PA-824), in which the OCH(2) linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved ( approximately 2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.

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Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase.

Publication Date: 2012 Jan 26 PMID: 22148323
Authors: Freeman-Cook, K. D. - Amor, P. - Bader, S. - Buzon, L. M. - Coffey, S. B. - Corbett, J. W. - Dirico, K. J. - Doran, S. D. - Elliott, R. L. - Esler, W. - Guzman-Perez, A. - Henegar, K. E. - Houser, J. A. - Jones, C. S. - Limberakis, C. - Loomis, K. - McPherson, K. - Murdande, S. - Nelson, K. L. - Phillion, D. - Pierce, B. S. - Song, W. - Sugarman, E. - Tapley, S. - Tu, M. - Zhao, Z.
Journal: J Med Chem

This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

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Synthesis and biological evaluation of antibody conjugates of phosphate prodrugs of cytotoxic DNA alkylators for the targeted treatment of cancer.

Publication Date: 2012 Jan 26 PMID: 22148292
Authors: Zhao, R. Y. - Erickson, H. K. - Leece, B. A. - Reid, E. E. - Goldmacher, V. S. - Lambert, J. M. - Chari, R. V.
Journal: J Med Chem

The synthesis and biological evaluation of phosphate prodrugs of analogues of 1 (CC-1065) and their conjugates with antibodies are described. The phosphate group on the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) portion of the compounds confers enhanced solubility and stability in aqueous solutions. In the presence of phosphatases, these compounds convert into active DNA-alkylating agents. The synthesis of the prodrugs was achieved sequentially through coupling of CBI with a bis-indolyl moiety, followed by attachment of a thiol-containing linker, and conversion of the hydroxyl group of CBI into a phosphate prodrug. The linkers incorporated into the prodrugs enable conjugation to an antibody via either a stable disulfide or thioether bond, in aqueous buffer solutions containing as little as 5% organic cosolvent, resulting in exclusively monomeric and stable antibody-cytotoxic prodrug conjugates. Two disulfide-containing linkers differing in the degree of steric hindrance were used in antibody conjugates to test the effect of different rates of intracellular disulfide cleavage and effector release on biological activity. The prodrugs can be converted to the active cytotoxic compounds through the action of endogenous phosphatases. Antibody-prodrug conjugates displayed potent antigen-selective cytotoxic activity in vitro and antitumor activity in vivo.

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Discovery of Kinase Spectrum Selective Macrocycle (16E)-14-Methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)] heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a Potent Inhibitor of Cyclin Dependent Kinases (CDKs), Janus Kinase 2 (JAK2), and Fms-like Tyrosine Kinase-3 (FLT3) for the Treatment of Cancer.

Publication Date: 2012 Jan 12 PMID: 22148278
Authors: William, A. D. - Lee, A. C. - Goh, K. C. - Blanchard, S. - Poulsen, A. - Teo, E. L. - Nagaraj, H. - Lee, C. P. - Wang, H. - Williams, M. - Sun, E. T. - Hu, C. - Jayaraman, R. - Pasha, M. K. - Ethirajulu, K. - Wood, J. M. - Dymock, B. W.
Journal: J Med Chem

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

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Nitric Oxide Release Is Not Required to Decrease the Ulcerogenic Profile of Nonsteroidal Anti-inflammatory Drugs.

Publication Date: 2012 Jan 26 PMID: 22148253
Authors: Jain, S. - Tran, S. - El Gendy, M. A. - Kashfi, K. - Jurasz, P. - Velazquez-Martinez, C. A.
Journal: J Med Chem

The objective of this work was to evaluate the biological properties of a new series of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) possessing a tyrosol linker between the NSAID and the NO-releasing moiety (PROLI/NO); however, initial screening of ester intermediates without the PROLI/NO group showed the required (desirable) efficacy/safety ratio, which questioned the need for NO in the design. In this regard, NSAID ester intermediates were potent and selective COX-2 inhibitors in vitro, showed equipotent anti-inflammatory activity compared to the corresponding parent NSAID, but showed a markedly reduced gastric toxicity when administered orally. These results provide complementary evidence to challenge the currently accepted notion that hybrid NO-NSAIDs exert their cytoprotective effects by releasing NO. Results obtained in this work constitute a good body of evidence to initiate a debate about the future replacement of NSAID prodrugs for unprotected NSAIDs (possessing a free carboxylic acid group) currently in clinical use.

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Identification of Novel alpha4beta2-Nicotinic Acetylcholine Receptor (nAChR) Agonists Based on an Isoxazole Ether Scaffold that Demonstrate Antidepressant-like Activity.

Publication Date: 2012 Jan 26 PMID: 22148173
Authors: Yu, L. F. - Tuckmantel, W. - Eaton, J. B. - Caldarone, B. - Fedolak, A. - Hanania, T. - Brunner, D. - Lukas, R. J. - Kozikowski, A. P.
Journal: J Med Chem

There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening toward other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested.

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Synthesis, Biological Evaluation, and Docking Studies of Tetrahydrofuran- Cyclopentanone- and Cyclopentanol-Based Ligands Acting at Adrenergic alpha(1)- and Serotonine 5-HT(1A) Receptors.

Publication Date: 2012 Jan 12 PMID: 22145629
Authors: Prandi, A. - Franchini, S. - Manasieva, L. I. - Fossa, P. - Cichero, E. - Marucci, G. - Buccioni, M. - Cilia, A. - Pirona, L. - Brasili, L.
Journal: J Med Chem

A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT(1A) receptors and alpha(1)-adrenoceptor subtypes was measured by binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone, or cyclopentanol moiety leads to an overall reduction of in vitro affinity at the alpha(1)-adrenoceptor while both potency and efficacy were increased at the 5-HT(1A) receptor. A significant improvement of 5-HT(1A)/alpha(1) selectivity was observed in some of the cyclopentanol derivatives synthesized (4acis, 4ccis and trans). Compounds 2a and 4ccis emerged as novel and interesting 5-HT(1A) receptor antagonist (pK(i) = 8.70) and a 5-HT(1A) receptor partial agonist (pK(i) = 9.25, pD(2) = 9.03, E(max) = 47%, 5-HT(1A)/alpha(1a) = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT(1A) agonism/antagonism activity.

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Structure-Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A(2A) and A(3) Adenosine Receptor Ligands.

Publication Date: 2012 Jan 12 PMID: 22142423
Authors: Hou, X. - Majik, M. S. - Kim, K. - Pyee, Y. - Lee, Y. - Alexander, V. - Chung, H. J. - Lee, H. W. - Chandra, G. - Lee, J. H. - Park, S. G. - Choi, W. J. - Kim, H. O. - Phan, K. - Gao, Z. G. - Jacobson, K. A. - Choi, S. - Lee, S. K. - Jeong, L. S.
Journal: J Med Chem

Truncated N(6)-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.

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Strategies to Mitigate the Bioactivation of 2-Anilino-7-Aryl-Pyrrolo[2,1-f][1,2,4]triazines: Identification of Orally Bioavailable, Efficacious ALK Inhibitors.

Publication Date: 2012 Jan 12 PMID: 22141319
Authors: Mesaros, E. F. - Thieu, T. V. - Wells, G. J. - Zificsak, C. A. - Wagner, J. C. - Breslin, H. J. - Tripathy, R. - Diebold, J. L. - McHugh, R. J. - Wohler, A. T. - Quail, M. R. - Wan, W. - Lu, L. - Huang, Z. - Albom, M. S. - Angeles, T. S. - Wells-Knecht, K. J. - Aimone, L. D. - Cheng, M. - Ator, M. A. - Ott, G. R. - Dorsey, B. D.
Journal: J Med Chem

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.

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Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides.

Publication Date: 2012 Jan 26 PMID: 22136469
Authors: Bamborough, P. - Diallo, H. - Goodacre, J. D. - Gordon, L. - Lewis, A. - Seal, J. T. - Wilson, D. M. - Woodrow, M. D. - Chung, C. W.
Journal: J Med Chem

Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.

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7,8-Dichloro-1-oxo-beta-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes.

Publication Date: 2012 Jan 12 PMID: 22136433
Authors: Huber, K. - Brault, L. - Fedorov, O. - Gasser, C. - Filippakopoulos, P. - Bullock, A. N. - Fabbro, D. - Trappe, J. - Schwaller, J. - Knapp, S. - Bracher, F.
Journal: J Med Chem

Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-beta-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.

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Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery.

Publication Date: 2012 Jan 26 PMID: 22136404
Authors: Chung, C. W. - Dean, A. W. - Woolven, J. M. - Bamborough, P.
Journal: J Med Chem

Bromodomain-containing proteins are key epigenetic regulators of gene transcription and readers of the histone code. However, the therapeutic benefits of modulating this target class are largely unexplored due to the lack of suitable chemical probes. This article describes the generation of lead molecules for the BET bromodomains through screening a fragment set chosen using structural insights and computational approaches. Analysis of 40 BRD2/fragment X-ray complexes highlights both shared and disparate interaction features that may be exploited for affinity and selectivity. Six representative crystal structures are then exemplified in detail. Two of the fragments are completely new bromodomain chemotypes, and three have never before been crystallized in a bromodomain, so our results significantly extend the limited public knowledge-base of crystallographic small molecule/bromodomain interactions. Certain fragments (including paracetamol) bind in a consistent mode to different bromodomains such as CREBBP, suggesting their potential to act as generic bromodomain templates. An important implication is that the bromodomains are not only a phylogenetic family but also a system in which chemical and structural knowledge of one bromodomain gives insights transferrable to others.

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Opioid Activity of Spinally Selective Analogues of N-Naphthoyl-beta-naltrexamine in HEK-293 Cells and Mice.

Publication Date: 2012 Jan 26 PMID: 22136373
Authors: Le Naour, M. - Lunzer, M. M. - Powers, M. D. - Portoghese, P. S.
Journal: J Med Chem

Using the selective mu-kappa agonist, N-naphthoyl-beta-naltrexamine 1, as the prototype ligand, a series of closely related naphthalene analogues were synthesized to study the chemical space around the naphthalene moiety in an effort to evaluate how receptor selectivity is affected by chemical modification. Nine analogues (2-10) of compound 1 were synthesized and tested on HEK-293 cells expressing homomeric and heteromeric opioid receptors, and in the mouse tail-flick assay. It was found that a small change in structure produces profound changes in selectivity in this series. This is exemplified by the discovery that introduction of a 6-fluoro group transforms 1 from a selective mu-kappa heteromeric receptor agonist to a delta-preferring agonist 7. The in vivo studies reveal that many of the ligands are more potent spinally than supraspinally and devoid of tolerance.

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Synthesis, Biological Evaluation, And Molecular Modeling of Chalcone Derivatives As Potent Inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatases (PtpA and PtpB).

Publication Date: 2012 Jan 12 PMID: 22136336
Authors: Chiaradia, L. D. - Martins, P. G. - Cordeiro, M. N. - Guido, R. V. - Ecco, G. - Andricopulo, A. D. - Yunes, R. A. - Vernal, J. - Nunes, R. J. - Terenzi, H.
Journal: J Med Chem

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC(50) values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.

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Synthesis and evaluation of 1,5-disubstituted tetrazoles as rigid analogues of combretastatin a-4 with potent antiproliferative and antitumor activity.

Publication Date: 2012 Jan 12 PMID: 22136312
Authors: Romagnoli, R. - Baraldi, P. G. - Salvador, M. K. - Preti, D. - Aghazadeh Tabrizi, M. - Brancale, A. - Fu, X. H. - Li, J. - Zhang, S. Z. - Hamel, E. - Bortolozzi, R. - Basso, G. - Viola, G.
Journal: J Med Chem

Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 4l significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 4l is a promising new antimitotic agent with clinical potential.

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Analogues of Orphan Nuclear Receptor Small Heterodimer Partner Ligand and Apoptosis Inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic Acid. 2. Impact of 3-Chloro Group Replacement on Inhibition of Proliferation and Induction of Apoptosis of Leukemia and Cancer Cell Lines.

Publication Date: 2012 Jan 12 PMID: 22136251
Authors: Xia, Z. - Correa, R. G. - Das, J. K. - Farhana, L. - Castro, D. J. - Yu, J. - Oshima, R. G. - Fontana, J. A. - Reed, J. C. - Dawson, M. I.
Journal: J Med Chem

The parent phenol of adapalene and its (E)-cinnamic acid analogue were found to induce cancer cell apoptosis but cause adverse systemic effects when administered to mice. In contrast, their respective 5-Cl- and 3-Cl-substituted analogues had their adverse effects mitigated without a comparable loss of cancer cell inhibitory activity. As a result, pharmacologic space in this region of the cinnamic phenyl ring scaffold was explored. Various substituents were introduced, and their effects on cancer cell proliferation and viability were evaluated. Cinnamic acids having 3-Br, CN, NO(2), NH(2), OMe, and N(3) groups had activity comparable to that of 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid. A comparative molecular field analysis study indicated that introduction of an H-bond acceptor at position 3 of the central phenyl ring would favor inhibition of leukemia cell viability, and docking suggested its hydrogen bonding with a polar group in a small heterodimer partner homology model. The 3-CN, NO(2), NH(2), and OH analogues also inhibited MMTV-Wnt1 murine mammary stem cell viability.

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Studies toward Novel Peptidomimetic Inhibitors of Thioredoxin-Thioredoxin Reductase System.

Publication Date: 2012 Jan 12 PMID: 22128876
Authors: Klossowski, S. - Muchowicz, A. - Firczuk, M. - Swiech, M. - Redzej, A. - Golab, J. - Ostaszewski, R.
Journal: J Med Chem

Thioredoxins (Trx) are ubiquitous multifunctional low-molecular weight proteins that together with thioredoxin reductases (TrxR) participate in the maintenance of protein thiol homeostasis in NADPH-dependent reactions. An increasing number of data reveal that the Trx-TrxR system is an attractive target for anticancer therapies. In this work, we have elaborated a new and simple synthetic approach employing Ugi reaction to synthesize several new inhibitors of this system. The influence of various electrophilic fragments of this new class of compounds on the inhibition of the Trx-TrxR system was evaluated. As a result, a new compound 19a (SK053), which inhibits the activity of the Trx-TrxR system and exhibits antitumor activity, was obtained. Biologic analyses revealed that 19a inhibits induction of NF-kappaB and AP-1 and decreases H(2)O(2) scavenging capacity in tumor cells. Altogether, we show that 19a is a novel potential antitumor peptidomimetic inhibitor that can be used as a starting compound for further optimization.

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(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent gamma-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction.

Publication Date: 2012 Jan 12 PMID: 22128851
Authors: Pan, Y. - Gerasimov, M. R. - Kvist, T. - Wellendorph, P. - Madsen, K. K. - Pera, E. - Lee, H. - Schousboe, A. - Chebib, M. - Brauner-Osborne, H. - Craft, C. M. - Brodie, J. D. - Schiffer, W. K. - Dewey, S. L. - Miller, S. R. - Silverman, R. B.
Journal: J Med Chem

Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115, compound 1) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. By use of in vivo microdialysis techniques in freely moving rats and microPET imaging techniques, 1 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at (1)/(300) to (1)/(600) the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose (1)/(300) that of vigabatrin. Electroretinographic (ERG) responses in rats treated with 1, at doses 20-40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, 1 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects.

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Malaria-Infected Mice Are Completely Cured by One 6 mg/kg Oral Dose of a New Monomeric Trioxane Sulfide Combined with Mefloquine.

Publication Date: 2012 Jan 12 PMID: 22128829
Authors: Slack, R. D. - Mott, B. T. - Woodard, L. E. - Triphati, A. - Sullivan, D. - Nenortas, E. - Girdwood, S. C. - Shapiro, T. A. - Posner, G. H.
Journal: J Med Chem

Sixteen new anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in Plasmodium berghei infected mice. Of these 16 new anilides administered orally as one 6 mg/kg dose combined with 18 mg/kg mefloquine hydrochloride, only sulfide 3-arteSanilide 12d was completely curative: on day 30 after infection, all mice in this group had no detectable parasitemia, gained as much weight as the uninfected control mice, and behaved normally.

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Design, Synthesis, and Evaluation of Thiol-Activated Sources of Sulfur Dioxide (SO(2)) as Antimycobacterial Agents.

Publication Date: 2012 Jan 12 PMID: 22128803
Authors: Malwal, S. R. - Sriram, D. - Yogeeswari, P. - Konkimalla, V. B. - Chakrapani, H.
Journal: J Med Chem

Here, 2,4-dinitrophenylsulfonamides with tunable cysteine-activated SO(2) release profiles with half-lives of SO(2) release varying from 2 to 63 min are reported. N-Benzyl-2,4-dinitrobenzenesulfonamide (6), which is prepared in one step from commercial sources, had a potency (MIC = 0.15 muM) of inhibiting Mycobacterium tuberculosis (Mtb) higher than the clinical agent isoniazid (MIC = 0.37 muM).

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Synthesis of rocaglamide hydroxamates and related compounds as eukaryotic translation inhibitors: synthetic and biological studies.

Publication Date: 2012 Jan 12 PMID: 22128783
Authors: Rodrigo, C. M. - Cencic, R. - Roche, S. P. - Pelletier, J. - Porco, J. A.
Journal: J Med Chem

The rocaglates/rocaglamides are a class of natural products known to display potent anticancer activity. One such derivative, silvestrol, has shown activity comparable to taxol in certain settings. Here, we report the synthesis of various rocaglamide analogues and identification of a hydroxamate derivative (-)-9 having activity similar to silvestrol in vitro and ex vivo for inhibition of protein synthesis. We also show that (-)-9 synergizes with doxorubicin in vivo to reduce Emu-Myc driven lymphomas.

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alpha-Aryl-N-alkyl Nitrones, as Potential Agents for Stroke Treatment: Synthesis, Theoretical Calculations, Antioxidant, Anti-inflammatory, Neuroprotective, and Brain-Blood Barrier Permeability Properties.

Publication Date: 2012 Jan 12 PMID: 22126405
Authors: Chioua, M. - Sucunza, D. - Soriano, E. - Hadjipavlou-Litina, D. - Alcazar, A. - Ayuso, I. - Oset-Gasque, M. J. - Gonzalez, M. P. - Monjas, L. - Rodriguez-Franco, M. I. - Marco-Contelles, J. - Samadi, A.
Journal: J Med Chem

We report the synthesis, theoretical calculations, the antioxidant, anti-inflammatory, and neuroprotective properties, and the ability to cross the blood-brain barrier (BBB) of (Z)-alpha-aryl and heteroaryl-N-alkyl nitrones as potential agents for stroke treatment. The majority of nitrones compete with DMSO for hydroxyl radicals, and most of them are potent lipoxygenase inhibitors. Cell viability-related (MTT assay) studies clearly showed that nitrones 1-3 and 10 give rise to significant neuroprotection. When compounds 1-11 were tested for necrotic cell death (LDH release test) nitrones 1-3, 6, 7, and 9 proved to be neuroprotective agents. In vitro evaluation of the BBB penetration of selected nitrones 1, 2, 10, and 11 using the PAMPA-BBB assay showed that all of them cross the BBB. Permeable quinoline nitrones 2 and 3 show potent combined antioxidant and neuroprotective properties and, therefore, can be considered as new lead compounds for further development in specific tests for potential stroke treatment.

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Conicasterol E, a Small Heterodimer Partner Sparing Farnesoid X Receptor Modulator Endowed with a Pregnane X Receptor Agonistic Activity, from the Marine Sponge Theonella swinhoei.

Publication Date: 2012 Jan 12 PMID: 22126372
Authors: Sepe, V. - Ummarino, R. - D'Auria, M. V. - Chini, M. G. - Bifulco, G. - Renga, B. - D'Amore, C. - Debitus, C. - Fiorucci, S. - Zampella, A.
Journal: J Med Chem

We report the isolation and pharmacological characterization of conicasterol E isolated from the marine sponge Theonella swinhoei. Pharmacological characterization of this steroid in comparison to CDCA, a natural FXR ligand, and 6-ECDCA, a synthetic FXR agonist generated by an improved synthetic strategy, and rifaximin, a potent PXR agonist, demonstrated that conicasterol E is an FXR modulator endowed with PXR agonistic activity. Conicasterol E induces the expression of genes involved in bile acids detoxification without effect on the expression of small heterodimer partner (SHP), thus sparing the expression of genes involved in bile acids biosynthesis. The relative positioning in the ligand binding domain of FXR, explored through docking calculations, demonstrated a different spatial arrangement for conicasterol E and pointed to the presence of simultaneous and efficient interactions with the receptor. In summary, conicasterol E represents a FXR modulator and PXR agonist that might hold utility in treatment of liver disorders.

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Diarylpropionitrile (DPN) Enantiomers: Synthesis and Evaluation of Estrogen Receptor beta-Selective Ligands.

Publication Date: 2012 Jan 12 PMID: 22122563
Authors: Carroll, V. M. - Jeyakumar, M. - Carlson, K. E. - Katzenellenbogen, J. A.
Journal: J Med Chem

Two estrogen receptor (ER) subtypes, ERalpha and ERbeta, mediate the actions of estrogens in diverse reproductive and nonreproductive target tissues. ER subtype-selective ligands, which bind to and activate these subtypes differentially, have proved to be useful in elucidating which actions of estrogens proceed through ERalpha vs ERbeta. Some of these ligands show potential as novel therapeutic agents. Diarylpropionitrile (DPN), an ERbeta selective ligand that we developed, is a chiral molecule, but it has been studied almost exclusively as the racemic mixture (rac-DPN, 1). Herein we report the development of an efficient enantioselective synthesis of the two isomers, R-DPN (3) and S-DPN (2), and we have compared the in vitro ligand binding affinities, coactivator binding affinities, recruitment potencies, and cellular transcriptional potencies of these isomers. Both enantiomers show a very high affinity and potency preference for ERbeta over ERalpha, typically in the range of 80-300-fold. Although the enantioselectivity is only modest (3-4-fold), the R-enantiomer is the higher affinity and more potent isomer. While ERbeta can be effectively and selectively stimulated by rac-DPN or by either R-DPN or S-DPN, R-DPN might be the preferred member of this isomeric series for biological studies of ERbeta function.

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In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.

Publication Date: 2012 Jan 12 PMID: 22122484
Authors: Fischer, H. - Atzpodien, E. A. - Csato, M. - Doessegger, L. - Lenz, B. - Schmitt, G. - Singer, T.
Journal: J Med Chem

Phospholipidosis (PLD) is a lysosomal storage disorder induced by compounds, notably cationic amphiphilic drugs, which although reversible interferes with cellular phospholipids.The in silico method described utilizes the amphiphilic moment DeltaDeltaG(AM) (kJ/mol) together with basic pK(a) values to assign PLD inducing potential to a compound. The new model was accurate and sensitive (85% and 82%, respectively) when compared to other data sets. Therefore, the parallel in vitro assay for PLD was discontinued. The data reinforce our view that the amphiphilic moment is far more informative for determining a compound's potential to induce PLD than the combined use of basic pK(a) and ClogP values.

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A New Generation of Radiofluorinated Pyrimidine-2,4,6-triones as MMP-Targeted Radiotracers for Positron Emission Tomography.

Publication Date: 2012 Jan 12 PMID: 22118188
Authors: Schrigten, D. - Breyholz, H. J. - Wagner, S. - Hermann, S. - Schober, O. - Schafers, M. - Haufe, G. - Kopka, K.
Journal: J Med Chem

Radiolabeled C-5-disubstituted pyrimidine-2,4,6-triones have recently been suggested by our group as a class of potent matrix metalloproteinase (MMP) targeted radiotracers that can noninvasively visualize activated MMPs by means of positron emission tomography (PET). MMPs belong to the zinc- and calcium-dependent endopeptidases which are involved in the proteolytic degradation of components of the extracellular matrix (ECM) but also are capable of processing and releasing bioactive molecules such as growth factors, proteinase inhibitors, and cytokines. Locally increased levels of activated MMPs modulate and contribute to the progression of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific and noninvasive visualization of aforementioned pathologies in vivo. On the basis of our recent results, we here describe a series of new fluorinated pyrimidine-2,4,6-triones of the second generation with maintained MMP inhibition potencies (IC(50) = 4-605 nM), which are fine-tuned toward more hydrophilic versions, and show the improved biodistribution behavior of one selected radiofluorinated pyrimidine-2,4,6-trione by means of small-animal PET.

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Molecular Basis of Structure-Activity Relationships between Salphen Metal Complexes and Human Telomeric DNA Quadruplexes.

Publication Date: 2012 Jan 12 PMID: 22112241
Authors: Campbell, N. H. - Karim, N. H. - Parkinson, G. N. - Gunaratnam, M. - Petrucci, V. - Todd, A. K. - Vilar, R. - Neidle, S.
Journal: J Med Chem

The first X-ray crystal structures of nickel(II) and copper(II) salphen metal complexes bound to a quadruplex DNA are presented. Two structures have been determined and show that these salphen-metal complexes bind to human telomeric quadruplexes by end-stacking, with the metal in each case almost in line with the potassium ion channel. Quadruplex and duplex DNA binding is presented for these two and other related salphen complexes, all with side-chains terminating in pyrrolidino end-groups and differing patterns of substitution on the salphen core. The crystal structures are able to provide rationalizations for the structure-activity data, and in particular for the superior quadruplex-binding of the nickel complexes compared to that of the copper-containing ones. The complexes show significant antiproliferative activity for the compounds in a panel of cancer cell lines. They also show telomerase inhibitory activity in the telomerase TRAP-LIG assay.

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Potent Galloyl-Based Selective Modulators Targeting Multidrug Resistance Associated Protein 1 and P-glycoprotein.

Publication Date: 2012 Jan 12 PMID: 22112208
Authors: Pellicani, R. Z. - Stefanachi, A. - Niso, M. - Carotti, A. - Leonetti, F. - Nicolotti, O. - Perrone, R. - Berardi, F. - Cellamare, S. - Colabufo, N. A.
Journal: J Med Chem

The multifactorial nature of chemotherapy failure in controlling cancer is often associated with the occurrence of multidrug resistance (MDR), a phenomenon likely related to the increased expression of members of the ATP binding cassette (ABC) transporter superfamily. In this respect, the most extensively characterized MDR transporters include ABCB1 (also known as MDR1 or P-glycoprotein) and ABCC1 (also known as MRP1) whose inhibition remains a priority to circumvent drug resistance. Herein, we report how the simple galloyl benzamide scaffold can be easily and properly decorated for the preparation of either MRP1 or P-gp highly selective inhibitors. In particular, some gallamides and pyrogallol-1-monomethyl ethers showed remarkable affinity and selectivity toward MRP1. On the other hand, trimethyl ether galloyl anilides, with few exceptions, exhibited moderate to very high and selective P-gp inhibition.

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Piperazine-2,3-dicarboxylic Acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors.

Publication Date: 2012 Jan 12 PMID: 22111545
Authors: Irvine, M. W. - Costa, B. M. - Dlaboga, D. - Culley, G. R. - Hulse, R. - Scholefield, C. L. - Atlason, P. - Fang, G. - Eaves, R. - Morley, R. - Mayo-Martin, M. B. - Amici, M. - Bortolotto, Z. A. - Donaldson, L. - Collingridge, G. L. - Molnar, E. - Monaghan, D. T. - Jane, D. E.
Journal: J Med Chem

Competitive N-methyl-d-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N(1)-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype selectivity among the more distantly related kainate receptor family. Compounds 18i and (-)-4 were the most potent kainate receptor antagonists, and 18i was selective for GluK1 versus GluK2, GluK3 and AMPA receptors. Modeling studies revealed structural features required for activity at GluK1 subunits and suggested that S674 was vital for antagonist activity. Consistent with this hypothesis, replacing the equivalent residue in GluK3 (alanine) with a serine imparts 18i antagonist activity. Antagonists with dual GluN2D and GluK1 antagonist activity may have beneficial effects in various neurological disorders. Consistent with this idea, antagonist 18i (30 mg/kg ip) showed antinociceptive effects in an animal model of mild nerve injury.

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Boranophosphate Isoster Controls P2Y-Receptor Subtype Selectivity and Metabolic Stability of Dinucleoside Polyphosphate Analogues.

Publication Date: 2012 Jan 12 PMID: 22107038
Authors: Yelovitch, S. - Camden, J. - Weisman, G. A. - Fischer, B.
Journal: J Med Chem

Dinucleoside polyphosphates, Np(n)N', exert their physiological effects via P2 receptors (P2Rs). Np(n)N' are attractive drug candidates as they offer better stability and specificity compared to nucleotides, the most common P2R ligands. To further improve the agonist properties of Np(n)N', we synthesized novel isosters of dinucleoside polyphosphates where N and N' are A or U and where the Palpha or Pbeta phosphate groups are replaced by boranophosphate, denoted as Np(n)(alpha-B)N' or Np(n)(beta-B)N' (n = 3, 4), respectively. The potency of Np(n)(alpha/beta-B)N' analogues was evaluated at tP2Y(1), hP2Y(2), hP2Y(4), and rP2Y(6) receptors. The most potent P2Y(1)R and P2Y(6)R agonists were the Up(4)(beta-B)A (A isomer, EC(50) of 0.5 muM vs 0.004 muM for 2-SMe-ADP) and Up(3)(alpha-B)U (B isomer, EC(50) of 0.3 muM vs 0.2 muM for UDP), respectively. The receptor subtype selectivity is controlled by the position of the borano moiety on the Np(n)N' polyphosphate chain and the type of the nucleobase. In addition, Np(n)(alpha/beta-B)N' proved approximately 22-fold more resistant to hydrolysis by e-NPP1, as compared to the corresponding Np(n)N' analogues. In summary, Up(4)(beta-B)A and Up(3)(alpha-B)U are potent, stable, and highly selective P2Y(1) and P2Y(6) receptor agonists, respectively.

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Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H(3) Receptor Antagonists with Potent Cognition Enhancing Activity.

Publication Date: 2012 Jan 12 PMID: 22107017
Authors: Tao, M. - Aimone, L. D. - Huang, Z. - Mathiasen, J. - Raddatz, R. - Lyons, J. - Hudkins, R. L.
Journal: J Med Chem

Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K(i) = 2.8 nM) and rat H(3)Rs (rH(3)R K(i) = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R(2) and R(6) positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyri dazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH(3)R K(i) = 1.7 nM, rH(3)R K(i) = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H(3)R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.

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Evaluation of Molecular Modeling of Agonist Binding in Light of the Crystallographic Structure of an Agonist-Bound A(2A) Adenosine Receptor.

Publication Date: 2012 Jan 12 PMID: 22104008
Authors: Deflorian, F. - Kumar, T. S. - Phan, K. - Gao, Z. G. - Xu, F. - Wu, H. - Katritch, V. - Stevens, R. C. - Jacobson, K. A.
Journal: J Med Chem

Molecular modeling of agonist binding to the human A(2A) adenosine receptor (AR) was assessed and extended in light of crystallographic structures. Heterocyclic adenine nitrogens of cocrystallized agonist overlaid corresponding positions of the heterocyclic base of a bound triazolotriazine antagonist, and ribose moiety was coordinated in a hydrophilic region, as previously predicted based on modeling using the inactive receptor. Automatic agonist docking of 20 known potent nucleoside agonists to agonist-bound A(2A)AR crystallographic structures predicted new stabilizing protein interactions to provide a structural basis for previous empirical structure activity relationships consistent with previous mutagenesis results. We predicted binding of novel C2 terminal amino acid conjugates of A(2A)AR agonist CGS21680 and used these models to interpret effects on binding affinity of newly synthesized agonists. d-Amino acid conjugates were generally more potent than l-stereoisomers and free terminal carboxylates more potent than corresponding methyl esters. Amino acid moieties were coordinated close to extracellular loops 2 and 3. Thus, molecular modeling is useful in probing ligand recognition and rational design of GPCR-targeting compounds with specific pharmacological profiles.

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Cyclobutane derivatives as novel nonpeptidic small molecule agonists of glucagon-like Peptide-1 receptor.

Publication Date: 2012 Jan 12 PMID: 22103243
Authors: Liu, Q. - Li, N. - Yuan, Y. - Lu, H. - Wu, X. - Zhou, C. - He, M. - Su, H. - Zhang, M. - Wang, J. - Wang, B. - Wang, Y. - Ma, D. - Ye, Y. - Weiss, H. C. - Gesing, E. R. - Liao, J. - Wang, M. W.
Journal: J Med Chem

A novel cyclobutane class of nonpeptidic glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by 3, was identified using receptor binding and multiple response element/cAMP response element (MRE/CRE)-driven reporter gene assays. The structures of 3 and its three isomers were elucidated by NMR, HRESIMS, and X-ray crystallography. A series of structural modifications were also made based on the core structure of 3 with different substitution groups at the west and east ends. Among these analogues, compound 16 was found to be 4- to 5-fold more potent than 3 both in vitro and in vivo.

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Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.

Publication Date: 2012 Jan 12 PMID: 22098589
Authors: Flipo, M. - Desroses, M. - Lecat-Guillet, N. - Villemagne, B. - Blondiaux, N. - Leroux, F. - Piveteau, C. - Mathys, V. - Flament, M. P. - Siepmann, J. - Villeret, V. - Wohlkonig, A. - Wintjens, R. - Soror, S. H. - Christophe, T. - Jeon, H. K. - Locht, C. - Brodin, P. - Deprez, B. - Baulard, A. R. - Willand, N.
Journal: J Med Chem

Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore, a second phase of optimization was required. Herein a structure-property relationship study is reported according to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration.

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Myelin Imaging Compound (MIC) Enhanced Magnetic Resonance Imaging of Myelination.

Publication Date: 2012 Jan 12 PMID: 22098543
Authors: Frullano, L. - Zhu, J. - Wang, C. - Wu, C. - Miller, R. H. - Wang, Y.
Journal: J Med Chem

The vertebrate nervous system is characterized by myelination, a fundamental biological process that protects the axons and facilitates electric pulse transduction. Damage to myelin is considered a major effect of autoimmune diseases such as multiple sclerosis (MS). Currently, therapeutic interventions are focused on protecting myelin integrity and promoting myelin repair. These efforts need to be accompanied by an effective imaging tool that correlates the disease progression with the extent of myelination. To date, magnetic resonance imaging (MRI) is the primary imaging technique to detect brain lesions in MS. However, conventional MRI cannot differentiate demyelinated lesions from other inflammatory lesions and therefore cannot predict disease progression in MS. To address this problem, we have prepared a Gd-based contrast agent, termed MIC (myelin imaging compound), which binds to myelin with high specificity. In this work, we demonstrate that MIC exhibits a high kinetic stability toward transmetalation with promising relaxometric properties. MIC was used for in vivo imaging of myelination following intracerebroventricular infusion in the rat brain. MIC was found to distribute preferentially in highly myelinated regions and was able to detect regions of focally induced demyelination.

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Cyclic Hydroxyamidines as Amide Isosteres: Discovery of Oxadiazolines and Oxadiazines as Potent and Highly Efficacious gamma-Secretase Modulators in Vivo.

Publication Date: 2012 Jan 12 PMID: 22098494
Authors: Sun, Z. Y. - Asberom, T. - Bara, T. - Bennett, C. - Burnett, D. - Chu, I. - Clader, J. - Cohen-Williams, M. - Cole, D. - Czarniecki, M. - Durkin, J. - Gallo, G. - Greenlee, W. - Josien, H. - Huang, X. - Hyde, L. - Jones, N. - Kazakevich, I. - Li, H. - Liu, X. - Lee, J. - Maccoss, M. - Mandal, M. B. - McCracken, T. - Nomeir, A. - Mazzola, R. - Palani, A. - Parker, E. M. - Pissarnitski, D. A. - Qin, J. - Song, L. - Terracina, G. - Vicarel, M. - Voigt, J. - Xu, R. - Zhang, L. - Zhang, Q. - Zhao, Z. - Zhu, X. - Zhu, Z.
Journal: J Med Chem

Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of gamma-secretase modulators leading to highly efficacious agents for reduction of central nervous system Abeta(42) in various animal models.

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Discovery of a Novel and Potent Class of F. tularensis Enoyl-Reductase (FabI) Inhibitors by Molecular Shape and Electrostatic Matching.

Publication Date: 2012 Jan 12 PMID: 22098466
Authors: Hevener, K. E. - Mehboob, S. - Su, P. C. - Truong, K. - Boci, T. - Deng, J. - Ghassemi, M. - Cook, J. L. - Johnson, M. E.
Journal: J Med Chem

Enoyl-acyl carrier protein (ACP) reductase, FabI, is a key enzyme in the bacterial fatty acid biosynthesis pathway (FAS II). FabI is an NADH-dependent oxidoreductase that acts to reduce enoyl-ACP substrates in a final step of the pathway. The absence of this enzyme in humans makes it an attractive target for the development of new antibacterial agents. FabI is known to be unresponsive to structure-based design efforts due to a high degree of induced fit and a mobile flexible loop encompassing the active site. Here we discuss the development, validation, and careful application of a ligand-based virtual screen used for the identification of novel inhibitors of the Francisella tularensis FabI target. In this study, four known classes of FabI inhibitors were used as templates for virtual screens that involved molecular shape and electrostatic matching. The program ROCS was used to search a high-throughput screening library for compounds that matched any of the four molecular shape queries. Matching compounds were further refined using the program EON, which compares and scores compounds by matching electrostatic properties. Using these techniques, 50 compounds were selected, ordered, and tested. The tested compounds possessed novel chemical scaffolds when compared to the input query compounds. Several hits with low micromolar activity were identified and follow-up scaffold-based searches resulted in the identification of a lead series with submicromolar enzyme inhibition, high ligand efficiency, and a novel scaffold. Additionally, one of the most active compounds showed promising whole-cell antibacterial activity against several Gram-positive and Gram-negative species, including the target pathogen. The results of a preliminary structure-activity relationship analysis are presented.

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Stilbene-Chalcone Hybrids: Design, Synthesis, and Evaluation as a New Class of Antimalarial Scaffolds That Trigger Cell Death through Stage Specific Apoptosis.

Publication Date: 2012 Jan 12 PMID: 22098429
Authors: Sharma, N. - Mohanakrishnan, D. - Shard, A. - Sharma, A. - Saima - Sinha, A. K. - Sahal, D.
Journal: J Med Chem

Novel stilbene-chalcone (S-C) hybrids were synthesized via a sequential Claisen-Schmidt-Knoevenagel-Heck approach and evaluated for antiplasmodial activity in in vitro red cell culture using SYBR Green I assay. The most potent hybrid (11) showed IC(50) of 2.2, 1.4, and 6.4 muM against 3D7 (chloroquine sensitive), Indo, and Dd2 (chloroquine resistant) strains of Plasmodium falciparum, respectively. Interestingly, the respective individual stilbene (IC(50) > 100 muM), chalcone (IC(50) = 11.5 muM), or an equimolar mixture of stilbene and chalcone (IC(50) = 32.5 muM) were less potent than 11. Studies done using specific stage enriched cultures and parasite in continuous culture indicate that 11 and 18 spare the schizont but block the progression of the parasite life cycle at the ring or the trophozoite stages. Further, 11 and 18 caused chromatin condensation, DNA fragmentation, and loss of mitochondrial membrane potential in Plasmodium falciparum, thereby suggesting their ability to cause apoptosis in malaria parasite.

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Comparative Study of the Affinity and Metabolism of Type I and Type II Binding Quinoline Carboxamide Analogues by Cytochrome P450 3A4.

Publication Date: 2012 Jan 12 PMID: 22087535
Authors: Dahal, U. P. - Joswig-Jones, C. - Jones, J. P.
Journal: J Med Chem

Compounds that coordinate to the heme-iron of cytochrome P450 (CYP) enzymes are assumed to increase metabolic stability. However, recently we observed that the type II binding quinoline carboxamide (QCA) compounds were metabolically less stable. To test if the higher intrinsic clearance of type II binding compounds relative to type I binding compounds is general for other metabolic transformations, we synthesized a library of QCA compounds that could undergo N-dealkylation, O-dealkylation, benzylic hydroxylation, and aromatic hydroxylation. The results demonstrated that type II binding QCA analogues were metabolically less stable (2- to 12-fold) at subsaturating concentration compared to type I binding counterparts for all the transformations. When the rates of different metabolic transformations between type I and type II binding compounds were compared, they were found to be in the order of N-demethylation > benzylic hydroxylation> O-demethylation > aromatic hydroxylation. Finally, for the QCA analogues with aza-heteroaromatic rings, we did not detect metabolism in aza-aromatic rings (pyridine, pyrazine, pyrimidine), indicating that electronegativity of the nitrogen can change regioselectivity in CYP metabolism.

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Synthesis, characterization and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity.

Publication Date: 2012 Jan 12 PMID: 22081932
Authors: Porcelli, L. - Gilardi, F. - Laghezza, A. - Piemontese, L. - Mitro, N. - Azzariti, A. - Altieri, F. - Cervoni, L. - Fracchiolla, G. - Giudici, M. - Guerrini, U. - Lavecchia, A. - Montanari, R. - Di Giovanni, C. - Paradiso, A. - Pochetti, G. - Simone, G. M. - Tortorella, P. - Crestani, M. - Loiodice, F.
Journal: J Med Chem

A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARgamma-ligand interactions, and docking experiments and X-ray studies were performed to explain the observed potency and efficacy. R-1 and S-1 were selected to evaluate several aspects of their biological activity. In an adipogenic assay, both enantiomers increased the expression of PPARgamma target genes and promoted the differentiation of 3T3-L1 fibroblasts to adipocytes. In vivo administration of these compounds to insulin resistant C57Bl/6J mice fed a high fat diet reduced visceral fat content and body weight. Examination of different metabolic parameters showed that R-1 and S-1 are insulin sensitizers. Notably, they also enhanced the expression of hepatic PPARalpha target genes indicating that their in vivo effects stemmed from an activation of both PPARalpha and gamma. Finally, the capability of R-1 and S-1 to inhibit cellular proliferation in colon cancer cell lines was also evaluated.

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Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry.

Publication Date: 2012 Jan 26 PMID: 22077389
Authors: Mendgen, T. - Steuer, C. - Klein, C. D.
Journal: J Med Chem

Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compounds that appear as "frequent hitters" in screening campaigns and therefore have little value in drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines and related compounds in screening campaigns, we decided to perform a systematic study on their promiscuity. An amount of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compounds were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compounds in published X-ray cocrystal structures were analyzed. The results indicate that the exocyclic, double bonded sulfur atom in rhodanines and thiohydantoins, in addition to other structural features, offers a particularly high density of interaction sites for polar interactions and hydrogen bonds. This causes a promiscuous behavior at concentrations in the "screening range" but should not be regarded as a general knockout criterion that excludes such screening hits from further development. It is suggested that special criteria for target affinity and selectivity are applied to these classes of compounds and that their exceptional and potentially valuable biomolecular binding properties are consequently exploited in a useful way.

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Discovery of a Potent and Orally Bioavailable Benzolactam-Derived Inhibitor of Polo-Like Kinase 1 (MLN0905).

Publication Date: 2012 Jan 12 PMID: 22070629
Authors: Duffey, M. O. - Vos, T. J. - Adams, R. - Alley, J. - Anthony, J. - Barrett, C. - Bharathan, I. - Bowman, D. - Bump, N. J. - Chau, R. - Cullis, C. - Driscoll, D. L. - Elder, A. - Forsyth, N. - Frazer, J. - Guo, J. - Guo, L. - Hyer, M. L. - Janowick, D. - Kulkarni, B. - Lai, S. J. - Lasky, K. - Li, G. - Li, J. - Liao, D. - Little, J. - Peng, B. - Qian, M. G. - Reynolds, D. J. - Rezaei, M. - Scott, M. P. - Sells, T. B. - Shinde, V. - Shi, Q. J. - Sintchak, M. D. - Soucy, F. - Sprott, K. T. - Stroud, S. G. - Nestor, M. - Visiers, I. - Weatherhead, G. - Ye, Y. - D'Amore, N.
Journal: J Med Chem

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.

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Low molecular weight phosphotyrosine protein phosphatases as emerging targets for the design of novel therapeutic agents.

Publication Date: 2012 Jan 12 PMID: 21988196
Authors: Maccari, R. - Ottana, R.
Journal: J Med Chem

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