J. Med. Chem.

New Angiopep-Modified Doxorubicin (ANG1007) and Etoposide (ANG1009) Chemotherapeutics With Increased Brain Penetration.

Publication Date: 2010 Mar 8 PMID: 20210346
Authors: Che, C. - Yang, G. - Thiot, C. - Lacoste, M. C. - Currie, J. C. - Demeule, M. - Regina, A. - Beliveau, R. - Castaigne, J. P.
Journal: J Med Chem

This report describes the synthesis and preliminary biological characterization of 2 (ANG1007) and 3 (ANG1009), two new chemical entities under development for the treatment of primary and secondary brain cancers. 2 consists of three doxorubicin molecules conjugated to Angiopep-2, a 19-mer peptide that crosses the blood-brain barrier (BBB) by an LRP-1 receptor-mediated transcytosis mechanism. 3 has a similar structure, with the exception that three etoposide moieties are conjugated to Angiopep-2. Both agents killed cancer cell lines in vitro with similar IC(50) values and with apparently similar cytotoxic mechanisms as unconjugated doxorubicin and etoposide. 2 and 3 exhibited dramatically higher BBB influx rate constants than unconjugated doxorubicin and etoposide and pooled within brain parenchymal tissue. Passage through the BBB was similar in Mdr1a (-/-) and wild type mice. These results provide further evidence of the potential of this drug development platform in the isolation of novel therapeutics with increased brain penetration.

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Radiosynthesis and Bioimaging of the Tuberculosis Chemotherapeutics Isoniazid, Rifampicin and Pyrazinamide in Baboons.

Publication Date: 2010 Mar 8 PMID: 20205479
Authors: Liu, L. - Xu, Y. - Shea, C. - Fowler, J. S. - Hooker, J. M. - Tonge, P. J.
Journal: J Med Chem

The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET). Each radiosynthesis and formulation has been accomplished in 1 h, using [(11)C]CH(3)I to label RIF and [(11)C]HCN to label INH and PZA. Following iv administration, INH, PZA, RIF, and/or their radiolabeled metabolites clear rapidly from many tissues; however, INH, PZA, and/or their radiolabeled metabolites accumulate in the bladder while RIF and/or its radiolabeled metabolites accumulates in the liver and gall bladder, consistent with the known routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood-brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the minimum inhibitory concentration (MIC) values for inhibiting bacterial growth of Mycobacterium tuberculosis (MTB). The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain and pave the way for imaging the distribution of the pathogen in vivo.

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Corrections to Cationic Amphiphile with Shikimic Acid Headgroup Shows More Systemic Promise Than Its Mannosyl Analogue as DNA Vaccine Carrier in Dendritic Cell Based Genetic Immunization.

Publication Date: 2010 Mar 5 PMID: 20205467
Authors: Srinivas, R. - Karmali, P. P. - Pramanik, D. - Garu, A. - Venkata Mahidhar, Y. - Majeti, B. K. - Ramakrishna, S. - Srinivas, G. - Chaudhuri, A.
Journal: J Med Chem

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Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-ylindole Analogues of Dacinostat (LAQ824).

Publication Date: 2010 Mar 5 PMID: 20205394
Authors: Cho, Y. S. - Whitehead, L. - Li, J. - Chen, C. H. - Jiang, L. - Vogtle, M. - Francotte, E. - Richert, P. - Wagner, T. - Traebert, M. - Lu, Q. - Cao, X. - Dumotier, B. - Fejzo, J. - Rajan, S. - Wang, P. - Yan-Neale, Y. - Shao, W. - Atadja, P. - Shultz, M.
Journal: J Med Chem

Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating hERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.

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Discovery, Biological Evaluation, and Structure-Activity Relationship of Amidine Based Sphingosine Kinase Inhibitors.

Publication Date: 2010 Mar 5 PMID: 20205392
Authors: Mathews, T. P. - Kennedy, A. J. - Kharel, Y. - Kennedy, P. C. - Nicoara, O. - Sunkara, M. - Morris, A. J. - Wamhoff, B. R. - Lynch, K. R. - Macdonald, T. L.
Journal: J Med Chem

Sphingosine 1-phosphate (S1P), a potent phospholipid growth and trophic factor, is synthesized in vivo by two sphingosine kinases. Thus these kinases have been proposed as important drug targets for treatment of hyperproliferative diseases and inflammation. We report here a new class of amidine-based sphingosine analogues that are competitive inhibitors of sphingosine kinases exhibiting varying degrees of enzyme selectivity. These inhibitors display K(I) values in the submicromolar range for both sphingosine kinases and, in cultured vascular smooth muscle cells, decrease S1P levels and initiate growth arrest.

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2009 Reviewers.

Publication Date: 2010 Mar 5 PMID: 20205390
Authors:
Journal: J Med Chem

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Sulfonamide Linked Neoglycoconjugates-A New Class of Inhibitors for Cancer-Associated Carbonic Anhydrases.

Publication Date: 2010 Mar 4 PMID: 20201556
Authors: Lopez, M. - Bornaghi, L. F. - Innocenti, A. - Vullo, D. - Charman, S. A. - Supuran, C. T. - Poulsen, S. A.
Journal: J Med Chem

The contribution of membrane-bound carbonic anhydrases (CAs) to hypoxic tumor growth and progression in cancer implicates cancer-associated CAs as a promising drug target for oncology. In this paper, we present a new class of sulfonamide-linked neoglycoconjugate that was designed to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. We describe the application of novel, yet straightforward, chemistry toward the synthesis of inhibitors that comprise both S-glycosyl sulfenamides and S-glycosyl sulfonamides. We also present the CA inhibition profile of our new neoglycoconjugates, more specifically a library of 30 compounds (3-32) that were designed to optimize both SAR (structure-activity relationship) and SPR (structure-property relationship) characteristics. We show that our approach produces neutral, water-soluble, and potent inhibitors (K(i)s in the low nanomolar range) that target cancer-associated CAs.

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Development of Novel, Highly Potent Inhibitors of V-RAF Murine Sarcoma Viral Oncogene Homologue B1 (BRAF): Increasing Cellular Potency through Optimization of a Distal Heteroaromatic Group.

Publication Date: 2010 Mar 3 PMID: 20199087
Authors: Suijkerbuijk, B. M. - Niculescu-Duvaz, I. - Gaulon, C. - Dijkstra, H. P. - Niculescu-Duvaz, D. - Menard, D. - Zambon, A. - Nourry, A. - Davies, L. - Manne, H. A. - Friedlos, F. - Ogilvie, L. M. - Hedley, D. - Lopes, F. - Preece, N. P. - Moreno-Farre, J. - Raynaud, F. I. - Kirk, R. - Whittaker, S. - Marais, R. - Springer, C. J.
Journal: J Med Chem

We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B-C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified (V600E)BRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated (V600E)BRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, (V600E)BRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo.

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In Vitro and In Vivo Photocytotoxicity of Boron Dipyrromethene Derivatives for Photodynamic Therapy.

Publication Date: 2010 Mar 3 PMID: 20199028
Authors: Lim, S. H. - Thivierge, C. - Nowak-Sliwinska, P. - Han, J. - van den Bergh, H. - Wagnieres, G. - Burgess, K. - Lee, H. B.
Journal: J Med Chem

To understand the effects of substitution patterns on photosensitizing the ability of boron dipyrromethene (BODIPY), two structural variations that either investigate the effectiveness of various iodinated derivatives to maximize the "heavy atom effect" or focus on the effect of extended conjugation at the 4-pyrrolic position to red-shift their activation wavelengths were investigated. Compounds with conjugation at the 4-pyrrolic position were less photocytotoxic than the parent unconjugated compound, while those with an iodinated BODIPY core presented better photocytotoxicity than compounds with iodoaryl groups at the meso-positions. The potency of the derivatives generally correlated well with their singlet oxygen generation level. Further studies of compound 5 on HSC-2 cells showed almost exclusive localization to mitochondria, induction of G(2)/M-phase cell cycle block, and onset of apoptosis. Compound 5 also extensively occluded the vasculature of the chick chorioallantoic membrane. Iodinated BODIPY structures such as compound 5 may have potential as new photodynamic therapy agents for cancer.

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Design, Synthesis, and Biological Evaluation of 3-[4-(2-Hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propox yethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a Potent, Orally Active, Brain Penetrant Inhibitor of Phosphodiesterase 5 (PDE5).

Publication Date: 2010 Mar 2 PMID: 20196613
Authors: Hughes, R. O. - Rogier, D. J. - Jacobsen, E. J. - Walker, J. K. - Macinnes, A. - Bond, B. R. - Zhang, L. L. - Yu, Y. - Zheng, Y. - Rumsey, J. M. - Walgren, J. L. - Curtiss, S. W. - Fobian, Y. M. - Heasley, S. E. - Cubbage, J. W. - Moon, J. B. - Brown, D. L. - Acker, B. A. - Maddux, T. M. - Tollefson, M. B. - Mischke, B. V. - Owen, D. R. - Freskos, J. N. - Molyneaux, J. M. - Benson, A. G. - Blevis-Bal, R. M.
Journal: J Med Chem

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propox yethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.

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Book Review of Comprehensive Organic Name Reactions and Reagents Comprehensive Organic Name Reactions and Reagents . By Zerong Wang John Wiley & Sons, Inc. , Hoboken, NJ . 2009 . xlix + 3661 pp. 18.5 x 26 cm. ISBN 978-0-471-70450-8 . $595.00.

Publication Date: 2010 Mar 2 PMID: 20196609
Authors: Kerns, R. J.
Journal: J Med Chem

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Structure-Activity Relationship of (N)-Methanocarba Phosphonate Analogues of 5'-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor.

Publication Date: 2010 Mar 1 PMID: 20192270
Authors: Kumar, T. S. - Zhou, S. Y. - Joshi, B. V. - Balasubramanian, R. - Yang, T. - Liang, B. T. - Jacobson, K. A.
Journal: J Med Chem

P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y(1) receptor). Two phosphonates, (1'S,2'R,3'S,4'R,5'S)-4'-(6-amino-2-chloropurin-9-yl)-2',3'-(dihydroxy)-1' -(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5'-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5'-extended phosphonates, all 2-H analogues, and a CH(3)-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.

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Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H(4) Receptor Inverse Agonists.

Publication Date: 2010 Mar 1 PMID: 20192225
Authors: Smits, R. A. - Adami, M. - Istyastono, E. P. - Zuiderveld, O. P. - van Dam, C. M. - de Kanter, F. J. - Jongejan, A. - Coruzzi, G. - Leurs, R. - de Esch, I. J.
Journal: J Med Chem

Hit optimization of the class of quinazoline containing histamine H(4) receptor (H(4)R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H(4)R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H(4)R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H(4)R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H(4)R affinity and behave as inverse agonists at the human H(4)R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanes ulfonamide (54) (pK(i) = 8.31 +/- 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.

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Fragment-Based Deconstruction of Bcl-x(L) Inhibitors.

Publication Date: 2010 Mar 1 PMID: 20192224
Authors: Barelier, S. - Pons, J. - Marcillat, O. - Lancelin, J. M. - Krimm, I.
Journal: J Med Chem

Fragment-based drug design consists of screening low-molecular-weight compounds in order to identify low-affinity ligands that are then modified or linked to yield potent inhibitors. The method thus attempts to build bioactive molecules in a modular way and relies on the hypothesis that the fragment binding mode will be conserved upon elaboration of the active molecule. If the inverse process is considered, do the fragments resulting from the deconstruction of high-affinity inhibitors recapitulate their binding mode in the large molecule? Few studies deal with this issue. Here, we report the analysis of 22 fragments resulting from the dissection of 9 inhibitors of the antiapoptotic protein Bcl-x(L). To determine if the fragments retained affinity toward the protein and identify their binding site, ligand-observed and protein-observed NMR experiments were used. The analysis of the fragments behavior illustrates the complexity of low-affinity protein-ligand interactions involved in the fragment-based construction of bioactive molecules.

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Discovery of a Biaryl Cyclohexene Carboxylic Acid (MK-6892): A Potent and Selective High Affinity Niacin Receptor Full Agonist with Reduced Flushing Profiles in Animals as a Preclinical Candidate.

Publication Date: 2010 Feb 25 PMID: 20184326
Authors: Shen, H. C. - Ding, F. X. - Raghavan, S. - Deng, Q. - Luell, S. - Forrest, M. J. - Carballo-Jane, E. - Wilsie, L. C. - Krsmanovic, M. L. - Taggart, A. K. - Wu, K. K. - Wu, T. J. - Cheng, K. - Ren, N. - Cai, T. Q. - Chen, Q. - Wang, J. - Wolff, M. S. - Tong, X. - Holt, T. G. - Waters, M. G. - Hammond, M. L. - Tata, J. R. - Colletti, S. L.
Journal: J Med Chem

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

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Identification of Inhibitors of Drug-Resistant Candida albicans Strains from a Library of Bicyclic Peptidomimetic Compounds.

Publication Date: 2010 Feb 25 PMID: 20184325
Authors: Trabocchi, A. - Mannino, C. - Machetti, F. - De Bernardis, F. - Arancia, S. - Cauda, R. - Cassone, A. - Guarna, A.
Journal: J Med Chem

The screening of a library of small molecule peptidomimetics toward secreted aspartic proteinase-2 (SAP2) of Candida albicans allowed us to identify two compounds that showed in vitro inhibitory potency comparable to pepstatin A. In an experimental model of vaginal candidiasis, the two candidate compounds were as active as a therapeutic dose of fluconazole. Importantly, this activity was fully preserved when the challenger was a fluconazole-resistant strain of the fungus. Altogether, our data demonstrate SAP2 as a valid C. albicans target for the development of new drugs against this important human pathogen.

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Fluorescent Epigenetic Small Molecule Induces Expression of the Tumor Suppressor Ras-Association Domain Family 1A and Inhibits Human Prostate Xenograft.

Publication Date: 2010 Feb 25 PMID: 20184324
Authors: Sheikh, K. D. - Banerjee, P. P. - Jagadeesh, S. - Grindrod, S. C. - Zhang, L. - Paige, M. - Brown, M. L.
Journal: J Med Chem

Epigenetic silencing of Ras-association domain family 1A (RASSF1A) protein in cancer cells results in a disruption of cell cycle control, genetic instability, enhanced cell motility, and apoptotic resistance. Ectopic expression of RASSF1A reverses this tumorigenic phenotype. Thus, small molecules with the ability to restore RASSF1A expression may represent a new class of therapeutic agents. Recently, we designed and synthesized a fluorescent carbazole analogue of mahanine (alkaloid from Murraya koenigii) that restored RASSF1A mRNA expression. Our fluorescent lead compound up-regulated RASSF1A in vitro, potently inhibited human prostate cancer cell proliferation, and fluoresced at a visible wavelength, allowing for the observation of intracellular distribution. The small molecule lead was not acutely toxic up to 550 mg/kg, and dosing at 10 mg/kg reduced human xenograft tumor volume by about 40%.

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Dopamine Receptor Ligands. Part 18: (1) Modification of the Structural Skeleton of Indolobenzazecine-Type Dopamine Receptor Antagonists.

Publication Date: 2010 Feb 24 PMID: 20180564
Authors: Robaa, D. - Enzensperger, C. - Abul Azm, S. E. - El Khawass, E. S. - El Sayed, O. - Lehmann, J.
Journal: J Med Chem

On the basis of the D(1/5)-selective dopamine antagonist LE 300 (1), an indolo[3,2-f]benzazecine derivative, we changed the annulation pattern of the heterocycles. The target compounds represent novel heterocyclic ring systems. The most constrained indolo[4,3a,3-ef]benzazecine 2 was inactive, but the indolo[4,3a,3-fg]benzazacycloundecene 3 showed antagonistic properties (functional Ca(2+) assay) with nanomolar affinities (radioligand binding) for all dopamine receptor subtypes, whereas the indolo[2,3-f]benzazecine 4 displayed a selectivity profile similar to 3 but with decreased affinities.

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Potent Arylsulfonamide Inhibitors of Tumor Necrosis Factor-alpha Converting Enzyme Able to Reduce Activated Leukocyte Cell Adhesion Molecule Shedding in Cancer Cell Models.

Publication Date: 2010 Feb 24 PMID: 20180536
Authors: Nuti, E. - Casalini, F. - Avramova, S. I. - Santamaria, S. - Fabbi, M. - Ferrini, S. - Marinelli, L. - La Pietra, V. - Limongelli, V. - Novellino, E. - Cercignani, G. - Orlandini, E. - Nencetti, S. - Rossello, A.
Journal: J Med Chem

Activated leukocyte cell adhesion molecule (ALCAM) plays a relevant role in tumor biology and progression. Our previous studies showed that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by nonspecific inhibitors of ADAM-17. For this reason, ADAM-17 may represent a new useful target in anticancer therapy. Herein, we report the synthesis and biological evaluation of new ADAM-17 inhibitors containing an arylsulfonamidic scaffold. Among the new potential inhibitors, two very promising compounds 17 and 18 were discovered, with a nanomolar activity for ADAM-17 isolated enzyme. These compounds proved to be also the most potent in inhibiting soluble ALCAM release in cancer cells, showing a nanomolar activity on A2774 and SKOV3 cell lines.

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Prediction and Evaluation of Protein Farnesyltransferase Inhibition by Commercial Drugs.

Publication Date: 2010 Feb 24 PMID: 20180535
Authors: Degraw, A. J. - Keiser, M. J. - Ochocki, J. D. - Shoichet, B. K. - Distefano, M. D.
Journal: J Med Chem

The similarity ensemble approach (SEA) relates proteins based on the set-wise chemical similarity among their ligands. It can be used to rapidly search large compound databases and to build cross-target similarity maps. The emerging maps relate targets in ways that reveal relationships one might not recognize based on sequence or structural similarities alone. SEA has previously revealed cross talk between drugs acting primarily on G-protein coupled receptors (GPCRs). Here we used SEA to look for potential off-target inhibition of the enzyme protein farnesyltransferase (PFTase) by commercially available drugs. The inhibition of PFTase has profound consequences for oncogenesis, as well as a number of other diseases. In the present study, two commercial drugs, Loratadine and Miconazole, were identified as potential ligands for PFTase and subsequently confirmed as such experimentally. These results point toward the applicability of SEA for the prediction of not only GPCR-GPCR drug cross talk but also GPCR-enzyme and enzyme-enzyme drug cross talk.

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Discovery of a Novel Series of Semisynthetic Vancomycin Derivatives Effective against Vancomycin-Resistant Bacteria.

Publication Date: 2010 Feb 24 PMID: 20180534
Authors: Nakama, Y. - Yoshida, O. - Yoda, M. - Araki, K. - Sawada, Y. - Nakamura, J. - Xu, S. - Miura, K. - Maki, H. - Arimoto, H.
Journal: J Med Chem

Novel semisynthetic vancomycin derivatives with antibacterial activity against vancomycin-resistant S. aureus (VRSA) were prepared. Replacement of Cl groups of vancomycin by Suzuki-Miyaura cross-coupling reaction, which gave the title compounds, is described for the first time. Introduction of a carbon substituent at the amino acid residue 2 of vancomycin led to an enhancement of antibacterial activity against vancomycin-resistant strains, whereas the additional introduction at the amino acid residue 6 resulted in a reduction in activity even against vancomycin-susceptible strains.

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Membrane Permeable Cyclic Peptidyl Inhibitors against Human Peptidylprolyl Isomerase Pin1.

Publication Date: 2010 Feb 24 PMID: 20180533
Authors: Liu, T. - Liu, Y. - Kao, H. Y. - Pei, D.
Journal: J Med Chem

Peptidylprolyl isomerase Pin1 regulates the function and/or stability of phosphoproteins by altering the conformation of specific pSer/pThr-Pro peptide bonds. In this work, a cyclic peptide library was synthesized and screened against the catalytic domain of human Pin1. The selected inhibitors contained a consensus motif of d-pThr-Pip-Nal (where Pip is l-piperidine-2-carboxylic acid and Nal is l-2-naphthylalanine). Representative compounds were tested for binding to Pin1 by isothermal titration calorimetry and inhibition of Pin1 activity, and the most potent inhibitors had K(D) (and K(I)) values in the low nanomolar range. Treatment of breast cancer cells with the inhibitors, which were rendered membrane permeable by attachment of an octaarginine sequence, inhibited cell proliferation and increased the protein levels of two previously established Pin1 substrates, PML and SMRT. Finally, a second generation of cell permeable Pin1 inhibitors was designed by replacing the noncritical residues within the cyclic peptide ring with arginine residues and shown to have antiproliferative activity against the cancer cells.

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Discovery of Dipeptides with High Affinity to the Specific Binding Site for Substance P(1-7).

Publication Date: 2010 Feb 23 PMID: 20178322
Authors: Fransson, R. - Botros, M. - Skold, C. - Nyberg, F. - Lindeberg, G. - Hallberg, M. - Sandstrom, A.
Journal: J Med Chem

Substance P 1-7 (SP(1-7), H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) is the major bioactive metabolite of substance P. The interest in this heptapeptide originates from the observation that it modulates, and in certain cases opposes the effects of the parent peptide, e.g., the nociceptive effect. The mu-opioid receptor agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH(2)) has been found to also interact with the specific binding site of SP(1-7) with only a 10-fold lower affinity compared to the native peptide. Considering the smaller size of EM-2 compared to the target heptapeptide, it was selected as a lead compound in the development of low-molecular-weight ligands to the SP(1-7) binding site. An alanine scan and truncation study led to the unexpected discovery of the dipeptide H-Phe-Phe-NH(2) (K(i) = 1.5 nM), having equal affinity as the endogenous heptapeptide SP(1-7.) Moreover, the studies show that the C-terminal phenylalanine amide is crucial for the affinity of the dipeptide.

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Discovery and SAR of Thiazolidine-2,4-dione Analogues as Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitors via Hierarchical Virtual Screening.

Publication Date: 2010 Feb 23 PMID: 20178321
Authors: Liu, X. - Xie, H. - Luo, C. - Tong, L. - Wang, Y. - Peng, T. - Ding, J. - Jiang, H. - Li, H.
Journal: J Med Chem

Insulin-like growth factor-1 receptor (IGF-1R) is a growth factor receptor tyrosine kinase acting as a critical mediator of cell proliferation and survival. Novel 5-benzylidenethiazolidine-2,4-dione (5) and 5-(furan-2-ylmethylene)thiazolidine-2,4-dione (6) compounds were identified as potent and selective IGF-1R inhibitors via hierarchical virtual screening. Initial SAR and biological activity of the analogues of 5 and 6 with thiazolidine-2,4-dione template are presented, and several inhibitors with low nanomolar potency are reported.

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Intramolecular Hydrogen Bonding in Medicinal Chemistry.

Publication Date: 2010 Feb 22 PMID: 20175530
Authors: Kuhn, B. - Mohr, P. - Stahl, M.
Journal: J Med Chem

The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. We study both aspects in detail with the aim of enabling a more rational use of this class of interactions in medicinal chemistry. On the basis of exhaustive searches in crystal structure databases, we derive propensities for intramolecular hydrogen bond formation of five- to eight-membered ring systems of relevance in drug discovery. A number of motifs, several of which are clearly underutilized in drug discovery, are analyzed in more detail by comparing small molecule and protein-ligand X-ray structures. To investigate effects on physicochemical properties, sets of closely related structures with and without the ability to form intramolecular hydrogen bonds were designed, synthesized, and characterized with respect to membrane permeability, water solubility, and lipophilicity. We find that changes in these properties depend on a subtle balance between the strength of the hydrogen bond interaction, geometry of the newly formed ring system, and the relative energies of the open and closed conformations in polar and unpolar environments. A number of general guidelines for medicinal chemists emerge from this study.

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A Novel Insulin Secretagogue Based on a Dinucleoside Polyphosphate Scaffold (1).

Publication Date: 2010 Feb 22 PMID: 20175517
Authors: Eliahu, S. - Barr, H. M. - Camden, J. - Weisman, G. A. - Fischer, B.
Journal: J Med Chem

Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5',5''-P(1),P(4),alpha,beta-methylene-tetraphosphate ), 8, (di-(2-MeS)-adenosine-5',5''-P(1),P(4),beta,gamma-methylene-tetraphosphate ), 9, and di-(2-MeS)-adenosine-5',5''-P(1),P(3),alpha,beta-methylene triphosphate, 10, were developed as potential insulin secretagogues. Analogues 8 and 9 were found to be agonists of the P2Y(1)R with EC(50) values of 0.42 and 0.46 muM, respectively, whereas analogue 10 had no activity. Analogues 8-10 were found to be completely resistant to hydrolysis by alkaline phosphatase over 3 h at 37 degrees C. Analogue 8 also was found to be 2.5-fold more stable in human blood serum than ATP, with a half-life of 12.1 h. Analogue 8 administration in rats caused a decrease in a blood glucose load from 155 mg/dL to ca. 100 mg/dL and increased blood insulin levels 4-fold as compared to basal levels. In addition, analogue 8 reduced a blood glucose load to normal values (80-110 mg/dL), unlike the commonly prescribed glibenclamide, which reduced glucose levels below normal values (60 mg/dL). These findings suggest that analogue 8 may prove to be an effective and safe treatment for type 2 diabetes.

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Synthesis, Biological Activity, and Molecular Modeling Studies of 1H-1,2,3-Triazole Derivatives of Carbohydrates as alpha-Glucosidases Inhibitors.

Publication Date: 2010 Feb 19 PMID: 20170190
Authors: Ferreira, S. B. - Sodero, A. C. - Cardoso, M. F. - Lima, E. S. - Kaiser, C. R. - Silva, F. P. - Ferreira, V. F.
Journal: J Med Chem

A class of drugs in use for treating type II diabetes mellitus (T2D), typified by the pseudotetrasaccharide acarbose, act by inhibiting the alpha-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Herein, we report the synthesis of a series of 4-substituted 1,2,3-triazoles conjugated with sugars, including d-xylose, d-galactose, d-allose, and d-ribose. Compounds were screened for alpha-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl-2,3-O-isopropylidene-beta-d-ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative, were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose. Docking studies on a MAL12 homology model disclosed a binding mode consistent with a transition-state-mimicking mechanism. Finally, the actual pharmacological potential of this triazole series was demonstrated by the reduction of postprandial blood glucose levels in normal rats. These compounds could represent new chemical scaffolds for developing novel drugs against T2D.

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1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Triple Reuptake Inhibitors.

Publication Date: 2010 Feb 19 PMID: 20170186
Authors: Micheli, F. - Cavanni, P. - Arban, R. - Benedetti, R. - Bertani, B. - Bettati, M. - Bettelini, L. - Bonanomi, G. - Braggio, S. - Checchia, A. - Davalli, S. - Di Fabio, R. - Fazzolari, E. - Fontana, S. - Marchioro, C. - Minick, D. - Negri, M. - Oliosi, B. - Read, K. D. - Sartori, I. - Tedesco, G. - Tarsi, L. - Terreni, S. - Visentini, F. - Zocchi, A. - Zonzini, L.
Journal: J Med Chem

The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.

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Development of Novel Adenosine Monophosphate-Activated Protein Kinase Activators.

Publication Date: 2010 Feb 19 PMID: 20170185
Authors: Guh, J. H. - Chang, W. L. - Yang, J. - Lee, S. L. - Wei, S. - Wang, D. - Kulp, S. K. - Chen, C. S.
Journal: J Med Chem

In light of the unique ability of thiazolidinediones to mediate peroxisome proliferator-activated receptor (PPAR)gamma-independent activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of interleukin (IL)-6 production, we conducted a screening of an in-house, thiazolidinedione-based focused compound library to identify novel agents with these dual pharmacological activities. Cell-based assays pertinent to the activation status of AMPK and mammalian homologue of target of rapamycin (i.e., phosphorylation of AMPK and p70 ribosomal protein S6 kinase, respectively) and IL-6/IL-6 receptor signaling (i.e., IL-6 production and signal transducer and activator of transcription 3 phosphorylation, respectively) in lipopolysaccharide (LPS)-stimulated THP-1 human macrophages were used to screen this compound library, which led to the identification of compound 53 (N-{4-[3-(1-methyl-cyclohexylmethyl)-2,4-dioxo-thiazolidin-5-ylidene-methy l]-phenyl}-4-nitro-3-trifluoro-methyl-benzenesulfonamide) as the lead agent. Evidence indicates that this drug-induced suppression of LPS-stimulated IL-6 production was attributable to AMPK activation. Furthermore, compound 53-mediated AMPK activation was demonstrated in C-26 colon adenocarcinoma cells, indicating that it is not a cell line-specific event.

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Noncovalent Tripeptidyl Benzyl- and Cyclohexyl-Amine Inhibitors of the Cysteine Protease Caspase-1.

Publication Date: 2010 Feb 19 PMID: 20170165
Authors: Loser, R. - Abbenante, G. - Madala, P. K. - Halili, M. - Le, G. T. - Fairlie, D. P.
Journal: J Med Chem

Potent and noncovalent inhibitors of caspase-1 were produced by incorporating a secondary amine (reduced amide) isostere in place of the conventional electrophile (e.g., aldehyde) that normally confers high potency to cysteine protease inhibitors. Benzyl- or cyclohexylamines produced potent, reversible, and competitive inhibitors that were selective for caspase-1 (e.g., K(i) = 47 nM) over caspases 3 and 8 with minimal cytotoxicity. Unlike most cysteine protease inhibitors, these compounds do not react covalently and indiscriminately with thiols.

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A New Class of Naphthalimide-Based Antitumor Agents That Inhibit Topoisomerase II and Induce Lysosomal Membrane Permeabilization and Apoptosis.

Publication Date: 2010 Feb 19 PMID: 20170164
Authors: Chen, Z. - Liang, X. - Zhang, H. - Xie, H. - Liu, J. - Xu, Y. - Zhu, W. - Wang, Y. - Wang, X. - Tan, S. - Kuang, D. - Qian, X.
Journal: J Med Chem

Based on the advantages of multitarget drugs for cancer treatment, a new class of naphthalimides was designed, synthesized, and proved to inhibit topoisomerase II (topo II), induced lysosomal membrane permeabilization (LMP), and ultimately caused apoptosis and cell death. The majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC(50) values ranging from 2 to 10 muM and are more active than amonafide, a naphthalimide that was in phase III clinical trials. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topo II inhibitors. Furthermore, compounds 7b-d were found to notably induce LMP and exhibited better antiproliferative activity compared with their single-target analogues. All of the newly synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.

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Identification of 2-Anilino-9-methoxy-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones as Dual PLK1/VEGF-R2 Kinase Inhibitor Chemotypes by Structure-Based Lead Generation.

Publication Date: 2010 Feb 19 PMID: 20170163
Authors: Egert-Schmidt, A. M. - Dreher, J. - Dunkel, U. - Kohfeld, S. - Preu, L. - Weber, H. - Ehlert, J. E. - Mutschler, B. - Totzke, F. - Schachtele, C. - Kubbutat, M. H. - Baumann, K. - Kunick, C.
Journal: J Med Chem

To develop multikinase inhibitors with dual PLK1/VEGF-R2 inhibitory activity, the d-annulated 1-benzazepin-2-one scaffold present in the paullone family of kinase inhibitors was investigated as a general structure template suitable for anchoring annulated heterocycles at the hinge region of the ATP binding site. For this purpose, the indole substructure of the paullones was replaced by other nitrogen containing heteroaromatics. The designed scaffolds were synthesized and tested on the indicated kinases. The 2-anilino-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones were found to be VEGF-R2 inhibitors with selectivity against the insulin receptor kinase. The attachment of a methoxy group to the 9-position of the scaffold led to additional PLK1 inhibitory activity, which was explained by an alternative binding mode of the 9-methoxy derivatives. Selected members of the compound class inhibited the VEGF-R2 autophosphorylation in human umbilical vein endothelial cells, the sprouting of human umbilical vein endothelial cell speroids, and the proliferation of diverse cancer cell lines.

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N-Methyl Phenylalanine-Rich Peptides as Highly Versatile Blood-Brain Barrier Shuttles.

Publication Date: 2010 Feb 19 PMID: 20170117
Authors: Malakoutikhah, M. - Prades, R. - Teixido, M. - Giralt, E.
Journal: J Med Chem

Here we studied the capacity of N-MePhe-(N-MePhe)(3)-CONH(2), Cha-(N-MePhe)(3)-CONH(2), and 2Nal-(N-MePhe)(3)-CONH(2) to carry various drugs (cargos) in in vitro blood-brain barrier (BBB) models in order to determine the versatility of these peptides as BBB-shuttles for drug delivery to the brain. Using SPPS, the peptides were coupled to GABA, Nip, and ALA to examine their passive BBB permeation by means of PAMPA and their lipophilicity by IAMC. Unaided, these nonpermeating drugs alone did not cross the PAMPA barrier and the BBB passively; however, the peptides tested as potential BBB shuttles transferred them by passive transfer through the PAMPA phospholipid. The permeability of peptides that showed the highest permeability in PAMPA, and Ac-N-MePhe-(N-MePhe)(3)-CONH(2) as the parent peptide was also examined in bovine brain microvessel endothelial cells (BBMECs). These peptide-based BBB shuttles open up the possibility to overcome the formidable obstacle of the BBB, thereby achieving drug delivery to the brain.

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5-Cyclic Amine-3-arylsulfonylindazoles as Novel 5-HT(6) Receptor Antagonists.

Publication Date: 2010 Feb 19 PMID: 20170099
Authors: Haydar, S. N. - Yun, H. - Andrae, P. M. - Mattes, J. - Zhang, J. - Kramer, A. - Smith, D. L. - Huselton, C. - Graf, R. - Aschmies, S. - Schechter, L. E. - Comery, T. A. - Robichaud, A. J.
Journal: J Med Chem

Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.

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Salicylic Acid Based Small Molecule Inhibitor for the Oncogenic Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2).

Publication Date: 2010 Feb 19 PMID: 20170098
Authors: Zhang, X. - He, Y. - Liu, S. - Yu, Z. - Jiang, Z. X. - Yang, Z. - Dong, Y. - Nabinger, S. C. - Wu, L. - Gunawan, A. M. - Wang, L. - Chan, R. J. - Zhang, Z. Y.
Journal: J Med Chem

The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors.

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Synthesis and Biological Activities of 2-Amino-1-arylidenamino Imidazoles as Orally Active Anticancer Agents.

Publication Date: 2010 Feb 19 PMID: 20170097
Authors: Li, W. T. - Hwang, D. R. - Song, J. S. - Chen, C. P. - Chuu, J. J. - Hu, C. B. - Lin, H. L. - Huang, C. L. - Huang, C. Y. - Tseng, H. Y. - Lin, C. C. - Chen, T. W. - Lin, C. H. - Wang, H. S. - Shen, C. C. - Chang, C. M. - Chao, Y. S. - Chen, C. T.
Journal: J Med Chem

2-Amino-1-arylidenaminoimidazoles, a novel class of orally (po) active microtubule-destabilizing anticancer agents, were synthesized. The compounds were designed from a hit compound identified in a drug discovery platform by using cancer cell-based high throughput screening assay. Selective synthesized compounds exerted cell cytotoxicity against human cancer cells. The underlying mechanisms for the anticancer activity were demonstrated as interacting with the tubulins and inhibiting microtubule assembly, leading to proliferation inhibition and apoptosis induction in the human tumor cells. Furthermore, two compounds showed in vivo anticancer activities in both po and intravenously (iv) administered routes and prolonged the life spans of murine leukemic P388 cells-inoculated mice. These new po active antimitotic anticancer agents are to be further examined in preclinical studies and developed for clinical uses.

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Novel Diamidino-Substituted Derivatives of Phenyl Benzothiazolyl and Dibenzothiazolyl Furans and Thiophenes: Synthesis, Antiproliferative and DNA Binding Properties.

Publication Date: 2010 Feb 19 PMID: 20170096
Authors: Racane, L. - Tralic-Kulenovic, V. - Kraljevic Pavelic, S. - Ratkaj, I. - Peixoto, P. - Nhili, R. - Depauw, S. - Hildebrand, M. P. - David-Cordonnier, M. H. - Pavelic, K. - Karminski-Zamola, G.
Journal: J Med Chem

A series of new diamidino-, diisopropylamidino-, and diimidazolinyl-substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes were successfully prepared and evaluated for their antiproliferative activity on tumor cell lines in vitro, DNA binding propensity, and sequence selectivity as well as cellular distribution. A strong antiproliferative effect of the tested compounds was observed on all tested cell lines in a concentration-dependent response pattern. In general, imidazolinyl-substituted derivatives and/or the thiophene core were in correlation with increased antiproliferative activity. Two compounds (2b and 3b) were chosen for biological studies due to their differential antiproliferative properties. The DNA binding properties of this new series of compounds were assessed and evidenced their efficient minor groove binding properties with preferential interaction at AT-rich sites. Both compounds also present nuclear subcellular localization, suggesting that their cellular mode of action implies localization in the DNA compartment and direct inhibition of DNA replication and induction of apoptosis.

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Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as Potent Carbonic Anhydrase Inhibitors: Synthesis, Biological Evaluation, and Enzyme-Ligand X-ray Studies.

Publication Date: 2010 Feb 19 PMID: 20170095
Authors: Gitto, R. - Agnello, S. - Ferro, S. - De Luca, L. - Vullo, D. - Brynda, J. - Mader, P. - Supuran, C. T. - Chimirri, A.
Journal: J Med Chem

Following previous studies we herein report the exploration of the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects and enzyme selectivity of a small class of 1-(cyclo)alkylisoquinolines containing a sulfonamide function considered a key feature for inhibiting CA. The results of enzymatic assays against human (h) CA isoforms, hCA I and hCA II (cytosolic, ubiquitous enzymes), hCA IX (transmembrane, tumor-associated), and hCA XIV (transmembrane), suggested that the presence of C-1 small substituents on isoquinoline scaffold controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, we report the X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, thus confirming the sulfonamide-zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor.

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Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5'-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound 26 (PKI-587), a Highly Efficacious Dual Inhibitor.

Publication Date: 2010 Feb 18 PMID: 20166697
Authors: Venkatesan, A. M. - Dehnhardt, C. M. - Delos Santos, E. - Chen, Z. - Dos Santos, O. - Ayral-Kaloustian, S. - Khafizova, G. - Brooijmans, N. - Mallon, R. - Hollander, I. - Feldberg, L. - Lucas, J. - Yu, K. - Gibbons, J. - Abraham, R. T. - Chaudhary, I. - Mansour, T. S.
Journal: J Med Chem

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpho lin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.

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Selectively nonselective kinase inhibition: striking the right balance.

Publication Date: 2010 Feb 25 PMID: 20166671
Authors: Morphy, R.
Journal: J Med Chem

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Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.

Publication Date: 2010 Feb 17 PMID: 20163176
Authors: McCauley, J. A. - McIntyre, C. J. - Rudd, M. T. - Nguyen, K. T. - Romano, J. J. - Butcher, J. W. - Gilbert, K. F. - Bush, K. J. - Holloway, M. K. - Swestock, J. - Wan, B. L. - Carroll, S. S. - Dimuzio, J. M. - Graham, D. J. - Ludmerer, S. W. - Mao, S. S. - Stahlhut, M. W. - Fandozzi, C. M. - Trainor, N. - Olsen, D. B. - Vacca, J. P. - Liverton, N. J.
Journal: J Med Chem

A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.

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The Discovery of 4-{1-[({2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amin o]cyclopropyl}benzoic Acid (MK-2894), A Potent and Selective Prostaglandin E(2) Subtype 4 Receptor Antagonist (dagger).

Publication Date: 2010 Mar 11 PMID: 20163116
Authors: Blouin, M. - Han, Y. - Burch, J. - Farand, J. - Mellon, C. - Gaudreault, M. - Wrona, M. - Levesque, J. F. - Denis, D. - Mathieu, M. C. - Stocco, R. - Vigneault, E. - Therien, A. - Clark, P. - Rowland, S. - Xu, D. - O'Neill, G. - Ducharme, Y. - Friesen, R.
Journal: J Med Chem

The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.

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Piracetam Defines a New Binding Site for Allosteric Modulators of alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic Acid (AMPA) Receptors.

Publication Date: 2010 Mar 11 PMID: 20163115
Authors: Ahmed, A. H. - Oswald, R. E.
Journal: J Med Chem

Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia. Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation. The pyrrolidine allosteric modulators, piracetam and aniracetam, were among the first of this class of drugs to be discovered. We have determined the structure of the ligand binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and a corresponding structure of GluA3 with aniracetam. Both drugs bind to GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity. However, the binding sites for piracetam and aniracetam differ considerably. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators. This new site may be of importance in the design of new allosteric regulators.

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Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic m(1) receptors.

Publication Date: 2010 Mar 11 PMID: 20158205
Authors: Fang, L. - Jumpertz, S. - Zhang, Y. - Appenroth, D. - Fleck, C. - Mohr, K. - Trankle, C. - Decker, M.
Journal: J Med Chem

A set of amide- and amine-linked hybrid molecules comprising moieties of the orthosteric M(1) muscarinic receptor agonist xanomeline and the cholinesterase inhibitor and allosteric receptor modulator tacrine were prepared with varying spacer length of 10-17 atoms. The hybrids inhibited acetylcholinesterase with similar or higher potency compared to tacrine. M(1) receptor binding affinity was similar or higher relative to xanomeline and far higher relative to tacrine. Affinities hardly changed when the receptors' orthosteric site was occupied by an inverse agonist ligand. When occupied by the orthosteric activator acetylcholine, affinity for the hybrids declined to unmeasureably low levels. Hybrids did not activate M(1) receptors. In vivo studies assaying cognition impairment in rats induced by scopolamine revealed pronounced enhancement of scopolamine action. Taken together, instead of dualsteric (simultaneous allosteric/orthosteric) binding, the hybrids seem to prefer purely allosteric binding at the inactive M(1) receptor.

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Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation.

Publication Date: 2010 Mar 11 PMID: 20158204
Authors: Carroll, F. I. - Blough, B. E. - Mascarella, S. W. - Navarro, H. A. - Eaton, J. B. - Lukas, R. J. - Damaj, M. I.
Journal: J Med Chem

Bupropion (2a) analogues were synthesized and tested for their ability to inhibit monoamine uptake and to antagonize the effects of human alpha3beta4*, alpha4beta2, alpha4beta4, and alpha1* nAChRs. The analogues were evaluated for their ability to block nicotine-induced effects in four tests in mice. Nine analogues showed increased monoamine uptake inhibition. Similar to 2a, all but one analogue show inhibition of nAChR function selective for human alpha3beta4*-nAChR. Nine analogues have higher affinity at alpha3beta4*-nAChRs than 2a. Four analogues also had higher affinity for alpha4beta2 nAChR. Analogues 2r, 2m, and 2n with AD(50) values of 0.014, 0.015, and 0.028 mg/kg were 87, 81, and 43 times more potent than 2a in blocking nicotine-induced antinociception in the tail-flick test. Analogue 2x with IC(50) values of 31 and 180 nM for DA and NE, respectively, and with IC(50) of 0.62 and 9.8 mum for antagonism of alpha3beta4 and alpha4beta2 nAChRs had the best overall in vitro profile relative to 2a.

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Structural insights into the design of small molecule inhibitors that selectively antagonize mcl-1.

Publication Date: 2010 Mar 11 PMID: 20158203
Authors: Bernardo, P. H. - Sivaraman, T. - Wan, K. F. - Xu, J. - Krishnamoorthy, J. - Song, C. M. - Tian, L. - Chin, J. S. - Lim, D. S. - Mok, H. Y. - Yu, V. C. - Tong, J. C. - Chai, C. L.
Journal: J Med Chem

The screening of a small focused library of rhodanine derivatives as inhibitors of Bcl-2 proteins led to the discovery of two structurally related compounds with different binding profiles against the Bcl-XL and the Mcl-1 proteins. Subsequent NMR studies with mutant proteins and in silico docking studies provide a possible rationale for the observed specificity.

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Structural Basis for Platelet Antiaggregation by Angiotensin II Type 1 Receptor Antagonist Losartan (DuP-753) via Glycoprotein VI.

Publication Date: 2010 Mar 11 PMID: 20158191
Authors: Ono, K. - Ueda, H. - Yoshizawa, Y. - Akazawa, D. - Tanimura, R. - Shimada, I. - Takahashi, H.
Journal: J Med Chem

GPVI is a key receptor for collagen-induced platelet activation. Loss or inhibition of GPVI causes only mildly prolonged bleeding times but prevents arterial thrombus formation in animal models. Therefore, GPVI is considered to be a potent target molecule for therapy of thrombotic diseases. Recently, it was reported that the AT(1)-receptor antagonist losartan (DuP-753) and EXP3179 inhibit platelet adhesion and aggregation via GPVI. However, it is still not clear how losartan is associated with inhibition of binding between GPVI and collagen at the molecular level. Here, we show by NMR that losartan directly interacts with the hydrophobic region consisting of strands C' and E in the N-terminal Ig-like domain of GPVI. A reliable GPVI-losartan complex model is presented by using a combination of NMR data and in silico tools. These data indicated that the phenyl group with the tetrazole ring in losartan plays a crucial role in the interaction with GPVI.

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Molecular Shape and Medicinal Chemistry: A Perspective.

Publication Date: 2010 Feb 16 PMID: 20158188
Authors: Nicholls, A. - McGaughey, G. B. - Sheridan, R. P. - Good, A. C. - Warren, G. - Mathieu, M. - Muchmore, S. W. - Brown, S. P. - Grant, J. A. - Haigh, J. A. - Nevins, N. - Jain, A. N. - Kelley, B.
Journal: J Med Chem

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1-Alkyl-4-phenyl-6-alkoxy-1H-quinazolin-2-ones: A Novel Series of Potent Calcium-Sensing Receptor Antagonists.

Publication Date: 2010 Mar 11 PMID: 20158186
Authors: Widler, L. - Altmann, E. - Beerli, R. - Breitenstein, W. - Bouhelal, R. - Buhl, T. - Gamse, R. - Gerspacher, M. - Halleux, C. - John, M. R. - Lehmann, H. - Kalb, O. - Kneissel, M. - Missbach, M. - Muller, I. R. - Reidemeister, S. - Renaud, J. - Taillardat, A. - Tommasi, R. - Weiler, S. - Wolf, R. M. - Seuwen, K.
Journal: J Med Chem

Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the bloodstream. Screening of the internal compound collection for inhibition of CaSR signaling function afforded 2a. In vitro potency could be improved >1000 fold by optimization of its chemical structure. The binding mode of our compounds was predicted based on molecular modeling and confirmed by testing with mutated receptors. While the compounds readily induced PTH release after iv application a special formulation was needed for oral activity. The required profile was achieved by using microemulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within minutes which reverted to baseline in about 1-2 h in both species.

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Cloning, Characterization, and Inhibition Studies of a beta-Carbonic Anhydrase from Brucella suis.

Publication Date: 2010 Mar 11 PMID: 20158185
Authors: Joseph, P. - Turtaut, F. - Ouahrani-Bettache, S. - Montero, J. L. - Nishimori, I. - Minakuchi, T. - Vullo, D. - Scozzafava, A. - Kohler, S. - Winum, J. Y. - Supuran, C. T.
Journal: J Med Chem

A beta-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA 1, has been cloned, purified, and characterized kinetically. bsCA 1 has appreciable activity as catalyst for the hydration of CO(2) to bicarbonate, with a k(cat) of 6.4 x 10(5) s(-1) and k(cat)/K(m) of 3.9 x 10(7) M(-1).s(-1). A panel of 38 sulfonamides and one sulfamate have been investigated for inhibition of this new beta-CA. All types of activities have been detected, with K(I)s in the range of 17 nM to 5.87 muM. The best bsCA 1 inhibitors were ethoxzolamide (17 nM), celecoxib (18 nM), dorzolamide (21 nM), valdecoxib, and sulpiride (19 nM). Whether bsCA 1 inhibitors may have application in the fight against brucellosis, an endemic disease and the major bacterial zoonosis, producing debilitating infection in humans and animals, warrants further studies.

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Synthesis, in Vitro and in Vivo Biological Evaluation, Docking Studies, and Structure-Activity Relationship (SAR) Discussion of Dipeptidyl Boronic Acid Proteasome Inhibitors Composed of beta-Amino Acids.

Publication Date: 2010 Mar 11 PMID: 20158184
Authors: Zhu, Y. - Zhu, X. - Wu, G. - Ma, Y. - Li, Y. - Zhao, X. - Yuan, Y. - Yang, J. - Yu, S. - Shao, F. - Li, R. - Ke, Y. - Lu, A. - Liu, Z. - Zhang, L.
Journal: J Med Chem

A series of novel dipeptidyl boronic acid proteasome inhibitors composed of beta-amino acids were synthesized, in vitro and in vivo biologically evaluated, and theoretically modeled for the first time. From the screened racemic compounds in enzyme, 4i was the most active. The IC(50) value of its pure enantiomer 4q was 9.6 nM, 36-fold more active than its isomer 4p and as active as the marketed bortezomib in inhibiting human 20S proteasome. This candidate also showed good activities with IC(50) values nearly less than 5 muM against several human solid and hematologic tumor cell lines. Safety evaluation in vivo with zebrafish and Sprague-Dawley (SD) rats showed that the candidate 4q was less toxic than bortezomib. Pharmacokinetic profiles suggested candidate 4q showed a more plasma exposure and longer half-life than bortezomib. Docking results indicated that 4q nearly interacted with 20S proteasome in a similar way as bortezomib.

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Direct determination of the insulin-insulin receptor interface using transferred cross-saturation experiments.

Publication Date: 2010 Mar 11 PMID: 20158183
Authors: Nakamura, T. - Takahashi, H. - Takahashi, M. - Shimba, N. - Suzuki, E. - Shimada, I.
Journal: J Med Chem

Insulin initiates metabolic control by binding to the insulin receptor (IR) on target cells. Kinetic and mutational analyses have revealed two binding sites on the insulin molecule and the residues that compose them. However, direct determination of the insulin-IR interface is required to distinguish those residues that contribute to receptor binding from those required for structural stability. Here, we successfully characterized one binding site using the nuclear magnetic resonance (NMR) transferred cross-saturation method, which can directly determine the binding interface of a large protein-protein complex. The results showed that this binding site contained three residues that have not been identified previously by mutational analyses. On the basis of the structure of the contact site, we also identified a molecule that can displace insulin from the IR. In addition, we discuss the mode of interaction between insulin and its receptor relative to the NMR analyses.

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Synthesis and biological evaluation of botulinum neurotoxin a protease inhibitors.

Publication Date: 2010 Mar 11 PMID: 20155918
Authors: Li, B. - Pai, R. - Cardinale, S. C. - Butler, M. M. - Peet, N. P. - Moir, D. T. - Bavari, S. - Bowlin, T. L.
Journal: J Med Chem

NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC(50) = 2.5 muM, FRET assay), which is 4.4-fold more potent than the lead structure and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.

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Synthesis and Evaluation of a Set of 4-Phenylpiperidines and 4-Phenylpiperazines as D(2) Receptor Ligands and the Discovery of the Dopaminergic Stabilizer 4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (Huntexil, Pridopidine, ACR16).

Publication Date: 2010 Feb 15 PMID: 20155917
Authors: Pettersson, F. - Ponten, H. - Waters, N. - Waters, S. - Sonesson, C.
Journal: J Med Chem

Modification of the partial dopamine type 2 receptor (D(2)) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D(2) antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D(2) in vitro, without displaying properties essential for interaction with D(2) in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D(2) antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D(2) antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The "agonist-like" kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D(2) antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique "dopaminergic stabilizer" characteristics, differentiating 12b from D(2) antagonists and partial D(2) agonists.

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Structure-based design, synthesis, and biological studies of new anticancer norindenoisoquinoline topoisomerase I inhibitors.

Publication Date: 2010 Mar 11 PMID: 20155916
Authors: Song, Y. - Shao, Z. - Dexheimer, T. S. - Scher, E. S. - Pommier, Y. - Cushman, M.
Journal: J Med Chem

On the basis of the superimposition of the crystal structures of norindenoisoquinoline 5 and topotecan (2) bound in the topoisomerase I-DNA covalent complex, as well as molecular docking and quantum chemical calculations, the substituted norindenoisoquinoline 14a was designed by transporting the 9-dimethylaminomethyl group of topotecan to the 10-position of the norindenoisoquinoline 5. The desired compound 14a was synthesized and found to possess topoisomerase I inhibitory activity that was slightly better than that of the starting compound 5. A focused set of 10-substitued norindenoisoquinoline analogues were then synthesized. The imidazole-substituted compound 14c was highly cytotoxic when evaluated in a series of human leukemia, ovarian, and breast cancer cells.

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Leech-Derived Thrombin Inhibitors: From Structures to Mechanisms to Clinical Applications.

Publication Date: 2010 Feb 15 PMID: 20155915
Authors: Corral-Rodriguez, M. A. - Macedo-Ribeiro, S. - Barbosa Pereira, P. J. - Fuentes-Prior, P.
Journal: J Med Chem

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Discovery of 4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides As Selective, Orally Active Inhibitors of Protein Kinase B (Akt).

Publication Date: 2010 Mar 11 PMID: 20151677
Authors: McHardy, T. - Caldwell, J. J. - Cheung, K. M. - Hunter, L. J. - Taylor, K. - Rowlands, M. - Ruddle, R. - Henley, A. - de Haven Brandon, A. - Valenti, M. - Davies, T. G. - Fazal, L. - Seavers, L. - Raynaud, F. I. - Eccles, S. A. - Aherne, G. W. - Garrett, M. D. - Collins, I.
Journal: J Med Chem

Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses.

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Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction.

Publication Date: 2010 Mar 11 PMID: 20151671
Authors: Jarvis, A. - Allerston, C. K. - Jia, H. - Herzog, B. - Garza-Garcia, A. - Winfield, N. - Ellard, K. - Aqil, R. - Lynch, R. - Chapman, C. - Hartzoulakis, B. - Nally, J. - Stewart, M. - Cheng, L. - Menon, M. - Tickner, M. - Djordjevic, S. - Driscoll, P. C. - Zachary, I. - Selwood, D. L.
Journal: J Med Chem

We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.

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Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion.

Publication Date: 2010 Mar 11 PMID: 20151670
Authors: Carmi, C. - Cavazzoni, A. - Vezzosi, S. - Bordi, F. - Vacondio, F. - Silva, C. - Rivara, S. - Lodola, A. - Alfieri, R. R. - La Monica, S. - Galetti, M. - Ardizzoni, A. - Petronini, P. G. - Mor, M.
Journal: J Med Chem

Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxir ane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.

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Corrections to discovery of leukotriene a4 hydrolase inhibitors using metabolomics biased fragment crystallography.

Publication Date: 2010 Mar 11 PMID: 20151668
Authors: Davies, D. R. - Mamat, B. - Magnusson, O. T. - Christensen, J. - Haraldsson, M. H. - Mishra, R. - Pease, B. - Hansen, E. - Singh, J. - Zembower, D. - Kim, H. - Kiselyov, A. S. - Burgin, A. B. - Gurney, M. E. - Stewart, L. J.
Journal: J Med Chem

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Synthesis and Uptake of Fluorescence-Labeled Combi-molecules by P-Glycoprotein-Proficient and -Deficient Uterine Sarcoma Cells MES-SA and MES-SA/DX5.

Publication Date: 2010 Mar 11 PMID: 20151639
Authors: Larroque-Lombard, A. L. - Todorova, M. - Golabi, N. - Williams, C. - Jean-Claude, B. J.
Journal: J Med Chem

Here, we report on the first synthesis of fluorescent-labeled epidermal growth factor receptor-DNA targeting combi-molecules, and we studied the influence of P-glycoprotein status of human sarcoma MES-SA cells on their growth inhibitory effect and cellular uptake. The results showed that 6, bearing a longer spacer between the quinazoline ring and the dansyl group, was more stable and more cytotoxic than 4. In contrast to the latter, it induced significant levels of DNA damage in human tumor cells. Moreover, in contrast to doxorubicin, a drug known to be actively effluxed by P-gp, the more stable combi-molecule 6 induced almost identical levels of drug uptake and DNA damage in P-gp-proficient and -deficient cells. Likewise, in contrast to doxorubicin, 4 and 6 exerted equal levels of antiproliferative activity against the two cell types. The results in toto suggest that despite their size, the antiproliferative effects of 4 and 6 were independent of P-gp status of the cells.

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N-Heterocyclic Carbene-Amine Pt(II) Complexes, a New Chemical Space for the Development of Platinum-Based Anticancer Drugs.

Publication Date: 2010 Mar 11 PMID: 20148592
Authors: Skander, M. - Retailleau, P. - Bourrie, B. - Schio, L. - Mailliet, P. - Marinetti, A.
Journal: J Med Chem

N-Heterocyclic carbene (NHC) platinum complexes have been highlighted as a promising and original platform for building new cytotoxic drugs of the cisplatin series. Mixed NHC-amine Pt(II) complexes have been prepared via a facile and modular two step sequence leading to trans-configured square planar species. They have been characterized by spectroscopic methods and X-ray diffraction studies. Their efficiency against both cisplatin sensitive (CEM and H460) and resistant (A2780/DDP, CH1/DDP, and SK-OV-3) cell lines has been demonstrated by in vitro experiments.

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Antitumor Agents. 272. Structure-Activity Relationships and In Vivo Selective Anti-Breast Cancer Activity of Novel Neo-tanshinlactone Analogues.

Publication Date: 2010 Mar 11 PMID: 20148565
Authors: Dong, Y. - Shi, Q. - Pai, H. C. - Peng, C. Y. - Pan, S. L. - Teng, C. M. - Nakagawa-Goto, K. - Yu, D. - Liu, Y. N. - Wu, P. C. - Bastow, K. F. - Morris-Natschke, S. L. - Brossi, A. - Lang, J. Y. - Hsu, J. L. - Hung, M. C. - Lee, E. Y. - Lee, K. H.
Journal: J Med Chem

Neo-tanshinlactone (1) and its previously reported analogues, such as 2, are potent and selective in vitro antibreast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure-activity relationships studies on these compounds revealed some key molecular determinants for this family of antibreast agents. Several derivatives (19-21 and 24) exerted potent and selective antibreast cancer activity with IC(50) values of 0.3, 0.2, 0.1, and 0.1 mug/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was 2- to 3-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analogue 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted.

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Highly Potent First Examples of Dual Aromatase-Steroid Sulfatase Inhibitors based on a Biphenyl Template (dagger).

Publication Date: 2010 Mar 11 PMID: 20148564
Authors: Woo, L. W. - Jackson, T. - Putey, A. - Cozier, G. - Leonard, P. - Acharya, K. R. - Chander, S. K. - Purohit, A. - Reed, M. J. - Potter, B. V.
Journal: J Med Chem

Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.

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BRAF Inhibitors Based on an Imidazo[4,5]pyridin-2-one Scaffold and a Meta Substituted Middle Ring.

Publication Date: 2010 Mar 11 PMID: 20148563
Authors: Nourry, A. - Zambon, A. - Davies, L. - Niculescu-Duvaz, I. - Dijkstra, H. P. - Menard, D. - Gaulon, C. - Niculescu-Duvaz, D. - Suijkerbuijk, B. M. - Friedlos, F. - Manne, H. A. - Kirk, R. - Whittaker, S. - Marais, R. - Springer, C. J.
Journal: J Med Chem

We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.

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5-amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors.

Publication Date: 2010 Mar 11 PMID: 20148562
Authors: Nien, C. Y. - Chen, Y. C. - Kuo, C. C. - Hsieh, H. P. - Chang, C. Y. - Wu, J. S. - Wu, S. Y. - Liou, J. P. - Chang, J. Y.
Journal: J Med Chem

A series of aroylquinoline derivatives were synthesized and evaluated for anticancer activity. 5-Amino-6-methoxy-2-aroylquinoline 15 showed more potent antiproliferative activity (IC(50) values ranging from 0.2 to 0.4 nM) as compared to 1a (combretastatin A-4) (IC(50) = 1.9-835 nM) against various human cancer cell lines and a MDR-resistant cancer cell line. Compound 15 (IC(50) = 1.6 muM) exhibited more potent inhibition of tubulin polymerization than 1a (IC(50) = 2.1 muM) and showed strong binding property to the colchicine binding site of microtubules.

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Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors.

Publication Date: 2010 Mar 11 PMID: 20148533
Authors: Muley, L. - Baum, B. - Smolinski, M. - Freindorf, M. - Heine, A. - Klebe, G. - Hangauer, D. G.
Journal: J Med Chem

Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per A(2) of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per A(2) demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.

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Development of Potent and Selective Inhibitors of ecto-5'-Nucleotidase Based on an Anthraquinone Scaffold.

Publication Date: 2010 Mar 11 PMID: 20146483
Authors: Baqi, Y. - Lee, S. Y. - Iqbal, J. - Ripphausen, P. - Lehr, A. - Scheiff, A. B. - Zimmermann, H. - Bajorath, J. - Muller, C. E.
Journal: J Med Chem

ecto-5'-Nucleotidase (eN, CD73) plays a major role in controlling extracellular adenosine levels. eN inhibitors have potential as novel drugs, for example, for the treatment of cancer. In the present study, we synthesized and investigated a series of 55 anthraquinone derivatives as potential inhibitors of eN, 11 of which are novel compounds and another 11 of which had previously been described but have now been synthesized by an improved method. We identified several potent inhibitors of rat eN. The most potent compounds were 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracen e-2-sulfonate (45, PSB-0952, K(i) = 260 nM) and 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfona te (52, PSB-0963, 150 nM), with 52 being the most potent eN inhibitor described to date. Selected compounds were further characterized and found to exhibit a competitive mechanism of inhibition. Investigations of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) and the P2Y receptor subtypes P2Y(2), P2Y(4), P2Y(6), and P2Y(12) showed that compound 45 exhibited the highest degree of selectivity (>150-fold).

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Discovery of 4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl) piperazin-1-yl)quinolin-8-ol and Its Analogues as Highly Potent Dopamine D2/D3 Agonists and as Iron Chelator: In Vivo Activity Indicates Potential Application in Symptomatic and Neuroprotective Therapy for Parkinson's Disease.

Publication Date: 2010 Mar 11 PMID: 20146482
Authors: Ghosh, B. - Antonio, T. - Reith, M. E. - Dutta, A. K.
Journal: J Med Chem

The role of iron in the pathogenesis of Parkinson's disease (PD) has been implicated strongly because of generation of oxidative stress leading to dopamine cell death. In our overall goal to develop bifunctional/multifunctional drugs, we designed dopamine D2/D3 agonist molecules with a capacity to bind to iron. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptor with tritiated spiperone to evaluate inhibition constants (K(i)). Functional activity of selected compounds was carried out with GTPgammaS binding assay. SAR results identified compounds (+)-19a and (-)-19b as two potent agonists for both D2 and D3 receptors (EC(50) (GTPgammaS); D2 = 4.51 and 1.69 nM and D3 = 1.58 and 0.74 nM for (-)-19b and (+)-19a, respectively). In vitro complexation studies with 19b demonstrated efficient chelation with iron. Furthermore, the deoxyribose assay with 19b demonstrated potent antioxidant activity. In PD animal model study, (-)-19b exhibited potent in vivo activity in reversing locomotor activity in reserpinized rats and also in producing potent rotational activity in 6-OHDA lesioned rats. This reports initial development of unique lead molecules that might find potential use in symptomatic and neuroprotective treatment of PD.

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Toward Biophysical Probes for the 5-HT(3) Receptor: Structure-Activity Relationship Study of Granisetron Derivatives.

Publication Date: 2010 Mar 11 PMID: 20146481
Authors: Vernekar, S. K. - Hallaq, H. Y. - Clarkson, G. - Thompson, A. J. - Silvestri, L. - Lummis, S. C. - Lochner, M.
Journal: J Med Chem

This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT(3)A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT(3)A receptors in mammalian cells.

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The Amino-Terminus of Angiotensin II Contacts Several Ectodomains of the Angiotensin II Receptor AT(1).

Publication Date: 2010 Mar 11 PMID: 20146480
Authors: Fillion, D. - Lemieux, G. - Basambombo, L. L. - Lavigne, P. - Guillemette, G. - Leduc, R. - Escher, E.
Journal: J Med Chem

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and major targets for drug development. Herein, we sought to identify the regions of the human angiotensin II (AngII) type 1 (hAT(1)) receptor binding cleft that interact with all positions of the AngII using photoaffinity labeling. We conducted a complete iterative walk-through of the AngII sequence with either p-benzoyl-l-phenylalanine (Bpa) or p-[3-(trifluoromethyl)-3H-diazirin-3-yl]-l-phenylalanine (Tdf) to yield two series of eight photoreactive analogues. Pharmacological properties assessment of these sixteen analogues showed that the CAM receptor has a structure-activity relationship (SAR) more amenable to the amino acid substitutions at positions 1, 2, 3, and 5 of AngII than the WT receptor. Photoaffinity labeling of the CAM receptor with the selected analogues, which exhibit different but complementary photochemical properties, suggested that the AngII amino-terminus resides in a hydrophilic environment and interacts simultaneously with different regions of the hAT(1) receptor, including several ectodomains.

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Design, Synthesis, and Evaluation of 2-Methyl- and 2-Amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as Ring-Constrained 2-Anilino-4-(thiazol-5-yl)pyrimidine Cyclin-Dependent Kinase Inhibitors.

Publication Date: 2010 Mar 11 PMID: 20146435
Authors: McIntyre, N. A. - McInnes, C. - Griffiths, G. - Barnett, A. L. - Kontopidis, G. - Slawin, A. M. - Jackson, W. - Thomas, M. - Zheleva, D. I. - Wang, S. - Blake, D. G. - Westwood, N. J. - Fischer, P. M.
Journal: J Med Chem

Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K(i) values. The most potent compound reported in this study inhibits CDK2 with an IC(50) of 0.7 nM ([ATP] = 100 muM). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A-CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket.

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Corrections to heat shock protein 90: inhibitors in clinical trials.

Publication Date: 2010 Mar 11 PMID: 20146424
Authors: Biamonte, M. A. - Van de Water, R. - Arndt, J. W. - Scannevin, R. H. - Perret, D. - Lee, W. C.
Journal: J Med Chem

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Biological and biophysical properties of the histone deacetylase inhibitor suberoylanilide hydroxamic Acid are affected by the presence of short alkyl groups on the phenyl ring.

Publication Date: 2010 Mar 11 PMID: 20143840
Authors: Oger, F. - Lecorgne, A. - Sala, E. - Nardese, V. - Demay, F. - Chevance, S. - Desravines, D. C. - Aleksandrova, N. - Guevel, R. L. - Lorenzi, S. - Beccari, A. R. - Barath, P. - Hart, D. J. - Bondon, A. - Carettoni, D. - Simonneaux, G. - Salbert, G.
Journal: J Med Chem

Inhibition of histone deacetylases (HDACs) leads to growth arrest, differentiation, or apoptosis of tumor cell lines, suggesting HDACs as promising targets for cancer therapy. At present, only one HDAC inhibitor (HDACi) is used in therapy: suberoylanilide hydroxamic acid (SAHA). Here, we describe the synthesis and biological evaluation of a new series of compounds derived from SAHA by substituting short alkyl chains at various positions of the phenyl ring. Such modifications induced variable effects ranging from partial loss of activity to increased potency. Through molecular modeling, we describe a possible interaction between HDAC7 proline 809, a residue that is strictly conserved within class 2 enzymes only, and the amide group of HDACi, while nuclear magnetic resonance experiments indicated that dimethyl m-substitution may stabilize the inhibitor in the active site. Our data provide novel information on the structure-activity relationship of HDACi and suggest new ways for developing second generation SAHA-like molecules.

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Discovery of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluoroph enyl)urea (Nelotanserin) and Related 5-Hydroxytryptamine(2A) Inverse Agonists for the Treatment of Insomnia.

Publication Date: 2010 Mar 11 PMID: 20143782
Authors: Teegarden, B. R. - Li, H. - Jayakumar, H. - Strah-Pleynet, S. - Dosa, P. I. - Selaya, S. D. - Kato, N. - Elwell, K. H. - Davidson, J. - Cheng, K. - Saldana, H. - Frazer, J. M. - Whelan, K. - Foster, J. - Espitia, S. - Webb, R. R. - Beeley, N. R. - Thomsen, W. - Morairty, S. R. - Kilduff, T. S. - Al-Shamma, H. A.
Journal: J Med Chem

Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluoroph enyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia.

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Synthesis and evaluation of paracetamol esters as novel Fatty Acid amide hydrolase inhibitors.

Publication Date: 2010 Mar 11 PMID: 20143779
Authors: Onnis, V. - Congiu, C. - Bjorklund, E. - Hempel, F. - Soderstrom, E. - Fowler, C. J.
Journal: J Med Chem

Fatty acid amide hydrolase (FAAH) is the key hydrolytic enzyme for the endogenous cannabinoid receptor ligand anandamide. The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described. Structure-activity relationship studies indicated that the ester (33) with a 2-(4-(2-(trifluoromethyl)pyridin-4-ylamino)phenyl)acetic acid substituent was the most potent analogue in this series. The compound inhibited FAAH activity in a competitive manner with a K(i) value of 0.16 muM. The compound was also able to inhibit the FAAH activity in rat basophilic leukemia cells as assessed by measuring either the hydrolysis of anandamide, the FAAH-dependent cellular accumulation of anandamide, or the FAAH-dependent recycling of tritium to the cell membranes. The compound also inhibited the activity of monoacylglycerol lipase (MGL), the enzyme responsible for the hydrolysis of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol, with an IC(50) value of 1.9 muM. It is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.

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Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanam ide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of Cancer.

Publication Date: 2010 Mar 11 PMID: 20143778
Authors: Cai, X. - Zhai, H. X. - Wang, J. - Forrester, J. - Qu, H. - Yin, L. - Lai, C. J. - Bao, R. - Qian, C.
Journal: J Med Chem

By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanam ide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compound that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.

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Piperazinyl Glutamate Pyridines as Potent Orally Bioavailable P2Y(12) Antagonists for Inhibition of Platelet Aggregation.

Publication Date: 2010 Mar 11 PMID: 20141147
Authors: Parlow, J. J. - Burney, M. W. - Case, B. L. - Girard, T. J. - Hall, K. A. - Harris, P. K. - Hiebsch, R. R. - Huff, R. M. - Lachance, R. M. - Mischke, D. A. - Rapp, S. R. - Woerndle, R. S. - Ennis, M. D.
Journal: J Med Chem

Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position of the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbony l)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavailability. Compound 47s was selected for further preclinical evaluations.

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Identification of Potent Pyrazolo[4,3-h]quinazoline-3-carboxamides as Multi-Cyclin-Dependent Kinase Inhibitors (dagger).

Publication Date: 2010 Mar 11 PMID: 20141146
Authors: Traquandi, G. - Ciomei, M. - Ballinari, D. - Casale, E. - Colombo, N. - Croci, V. - Fiorentini, F. - Isacchi, A. - Longo, A. - Mercurio, C. - Panzeri, A. - Pastori, W. - Pevarello, P. - Volpi, D. - Roussel, P. - Vulpetti, A. - Brasca, M. G.
Journal: J Med Chem

Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent.

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Incorporation of Fluorinated Phenylalanine Generates Highly Specific Inhibitor of Proteasome's Chymotrypsin-like Sites.

Publication Date: 2010 Mar 11 PMID: 20131905
Authors: Geurink, P. P. - Liu, N. - Spaans, M. P. - Downey, S. L. - van den Nieuwendijk, A. M. - van der Marel, G. A. - Kisselev, A. F. - Florea, B. I. - Overkleeft, H. S.
Journal: J Med Chem

Proteasomal processing is conducted by three individual catalytic subunits, namely beta1, beta2, and beta5. Subunit-specific inhibitors are useful tools in dissecting the role of these individual subunits and are leads toward the development of antitumor agents. We here report that the presence of fluorinated phenylalanine derivatives in peptide based proteasome inhibitors has a profound effect on inhibitor potency and selectivity. Specifically, compound 4a emerges as one of the most beta5 specific inhibitors known to date.

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1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as Potent and Selective Norepinephrine Reuptake Inhibitors.

Publication Date: 2010 Mar 11 PMID: 20131864
Authors: Vu, A. T. - Cohn, S. T. - Zhang, P. - Kim, C. Y. - Mahaney, P. E. - Bray, J. A. - Johnston, G. H. - Koury, E. J. - Cosmi, S. A. - Deecher, D. C. - Smith, V. A. - Harrison, J. E. - Leventhal, L. - Whiteside, G. T. - Kennedy, J. D. - Trybulski, E. J.
Journal: J Med Chem

Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.

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Photooxidation and Phototoxicity of pi-Extended Squaraines.

Publication Date: 2010 Mar 11 PMID: 20131844
Authors: Rapozzi, V. - Beverina, L. - Salice, P. - Pagani, G. A. - Camerin, M. - Xodo, L. E.
Journal: J Med Chem

This paper describes the synthesis of pi-extended squaraines and their photooxidation properties and gives an in-depth characterization of these molecules as photosensitizing agents. Squaraines show a strong absorption in the tissue transparency window (600-800 nm), and upon irradiation, they undergo a photooxidation process, leading to the formation of peroxide and hydroperoxide radicals according to a type I radical chain process. Confocal laser microscopy demonstrates that the designed squaraines efficiently internalize in the cytoplasm and not in the nucleus of the cell. In the dark, they are scarcely cytotoxic, but after irradition, they promote a strong dose-dependent phototoxic effect in four different cancer cells. In HeLa and MCF-7 cells, squaraines 4 and 5, thanks to their hydrocarbon tails, associate to the membranes and induce lipid peroxidation, as indicated by a marked increase of malonyldialdehyde after photodynamic treatment, in agreement with in vitro photooxidation studies. FACS, caspase-3/7 assays and time-lapse microscopy demonstrate that the designed squaraines cause cell death primarily by necrosis.

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Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids.

Publication Date: 2010 Mar 11 PMID: 20131843
Authors: Breuning, A. - Degel, B. - Schulz, F. - Buchold, C. - Stempka, M. - Machon, U. - Heppner, S. - Gelhaus, C. - Leippe, M. - Leyh, M. - Kisker, C. - Rath, J. - Stich, A. - Gut, J. - Rosenthal, P. J. - Schmuck, C. - Schirmeister, T.
Journal: J Med Chem

New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric E-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt)-OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing compounds, the maleic acid derivatives 42 and 43 (BnO-Phe<--Mal-Phe-OBn, BnO-Phe<--Mal-Phe-Ala-OBn, Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe<--Fum-Phe-OBn) only displayed inhibition of the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.

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Structure of human G protein-coupled receptor kinase 2 in complex with the kinase inhibitor balanol.

Publication Date: 2010 Feb 25 PMID: 20128603
Authors: Tesmer, J. J. - Tesmer, V. M. - Lodowski, D. T. - Steinhagen, H. - Huber, J.
Journal: J Med Chem

G protein-coupled receptor kinase 2 (GRK2) is a pharmaceutical target for the treatment of cardiovascular diseases such as congestive heart failure, myocardial infarction, and hypertension. To better understand how nanomolar inhibition and selectivity for GRK2 might be achieved, we have determined crystal structures of human GRK2 in complex with Gbetagamma in the presence and absence of the AGC kinase inhibitor balanol. The selectivity of balanol among human GRKs is assessed.

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New benzophenone-derived bisphosphonium salts as leishmanicidal leads targeting mitochondria through inhibition of respiratory complex II.

Publication Date: 2010 Feb 25 PMID: 20128602
Authors: Luque-Ortega, J. R. - Reuther, P. - Rivas, L. - Dardonville, C.
Journal: J Med Chem

A set of benzophenone-derived bisphosphonium salts was synthesized and assayed for lethal activity on the human protozoan parasite Leishmania. A subset of them, mostly characterized by phosphonium substituents with an intermediate hydrophobicity, inhibited parasite proliferation at low micromolar range of concentrations. The best of this subset, 4,4'-bis((tri-n-pentylphosphonium)methyl)benzophenone dibromide, showed a very scarce toxicity on mammalian cells. This compound targets complex II of the respiratory chain of the parasite, based on (i) a dramatically swollen mitochondrion in treated parasites, (ii) fast decrease of cytoplasmic ATP, (iii) a decrease of the electrochemical mitochondrial potential, and (iv) inhibition of the oxygen consumption rate using succinate as substrate. Thus, this type of compounds represents a new lead in the development of leishmanicidal drugs.

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Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth.

Publication Date: 2010 Feb 25 PMID: 20128596
Authors: Johnstone, K. D. - Karoli, T. - Liu, L. - Dredge, K. - Copeman, E. - Li, C. P. - Davis, K. - Hammond, E. - Bytheway, I. - Kostewicz, E. - Chiu, F. C. - Shackleford, D. M. - Charman, S. A. - Charman, W. N. - Harenberg, J. - Gonda, T. J. - Ferro, V.
Journal: J Med Chem

A series of polysulfated penta- and tetrasaccharide glycosides containing alpha(1-->3)/alpha(1-->2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2, and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.

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Design and synthesis of potent and selective BACE-1 inhibitors.

Publication Date: 2010 Feb 25 PMID: 20128595
Authors: Bjorklund, C. - Oscarson, S. - Benkestock, K. - Borkakoti, N. - Jansson, K. - Lindberg, J. - Vrang, L. - Hallberg, A. - Rosenquist, A. - Samuelsson, B.
Journal: J Med Chem

Highly potent BACE-1 protease inhibitors have been developed from an inhibitors containing a hydroxyethylene (HE) core displaying aryloxymethyl or benzyloxymethyl P1 side chain and a methoxy P1' side chain. The target molecules were synthesized in good overall yields from chiral carbohydrate starting materials. The inhibitors show high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnishes BACE-1 K(i) << 1 nM and displays >1000-fold selectivity over cathepsin D.

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Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist.

Publication Date: 2010 Feb 25 PMID: 20128594
Authors: Shearer, B. G. - Wiethe, R. W. - Ashe, A. - Billin, A. N. - Way, J. M. - Stanley, T. B. - Wagner, C. D. - Xu, R. X. - Leesnitzer, L. M. - Merrihew, R. V. - Shearer, T. W. - Jeune, M. R. - Ulrich, J. C. - Willson, T. M.
Journal: J Med Chem

4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPARdelta with good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPARdelta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPARdelta and inhibited basal CPT1a gene transcription. Compound 3 is a PPARdelta antagonist with utility as a tool to elucidate PPARdelta cell biology and pharmacology.

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Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.

Publication Date: 2010 Feb 25 PMID: 20121198
Authors: Wang, S. - Beck, R. - Blench, T. - Burd, A. - Buxton, S. - Malic, M. - Ayele, T. - Shaikh, S. - Chahwala, S. - Chander, C. - Holland, R. - Merette, S. - Zhao, L. - Blackney, M. - Watts, A.
Journal: J Med Chem

FIXa is a serine protease enzyme involved in the intrinsic pathway of the coagulation cascade. The upstream intervention of the coagulation cascade in selectively inhibiting FIXa would leave hemostasis intact via the extrinsic pathway, leading to an optimum combination of efficacy and safety with low incidence of bleeding. We have identified 2-amindinobenzothiophene template as a lead scaffold for FIXa inhibiton based on its homology with urokinase plasminogen activator (uPA). Subsequent SAR work on the template revealed a number of highly potent FIXa inhibitors, though with moderate selectivity against FXa. X-ray study with one of the analogues demonstrated active site binding interaction with the induced opening of the S1 beta pocket and a secondary binding at the S2-S4 sites, which is in direct contrast with the previous finding.

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Structure based drug design: development of potent and selective factor IXa (FIXa) inhibitors.

Publication Date: 2010 Feb 25 PMID: 20121197
Authors: Wang, S. - Beck, R. - Burd, A. - Blench, T. - Marlin, F. - Ayele, T. - Buxton, S. - Dagostin, C. - Malic, M. - Joshi, R. - Barry, J. - Sajad, M. - Cheung, C. - Shaikh, S. - Chahwala, S. - Chander, C. - Baumgartner, C. - Holthoff, H. P. - Murray, E. - Blackney, M. - Giddings, A.
Journal: J Med Chem

On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.

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Discovery of novel fibroblast growth factor receptor 1 kinase inhibitors by structure-based virtual screening.

Publication Date: 2010 Feb 25 PMID: 20121196
Authors: Ravindranathan, K. P. - Mandiyan, V. - Ekkati, A. R. - Bae, J. H. - Schlessinger, J. - Jorgensen, W. L.
Journal: J Med Chem

Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, respectively, were discovered that inhibit FGFR1 kinase with IC(50) values of 23 and 50 microM. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 microM. The core structures represent new structural motifs for FGFR1 kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek selectivity, and hit identification.

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Engineering galanin analogues that discriminate between GalR1 and GalR2 receptor subtypes and exhibit anticonvulsant activity following systemic delivery.

Publication Date: 2010 Feb 25 PMID: 20121116
Authors: Robertson, C. R. - Scholl, E. A. - Pruess, T. H. - Green, B. R. - White, H. S. - Bulaj, G.
Journal: J Med Chem

Galanin modulates seizures in the brain through two galanin receptor subtypes, GalR1 and GalR2. To generate systemically active galanin receptor ligands that discriminate between GalR1 and GalR2, the GalR1-preferring analogue Gal-B2 (or NAX 5055) was rationally redesigned to yield GalR2-preferring analogues. Systematic truncations of the N-terminal backbone led to [N-Me,des-Sar]Gal-B2, containing N-methyltryptophan. This analogue exhibited 18-fold preference in binding toward GalR2, maintained agonist activity, and exhibited potent anticonvulsant activity in mice following intraperitoneal administration.

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Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis.

Publication Date: 2010 Feb 25 PMID: 20121115
Authors: Wang, H. - Luo, X. - Ye, M. - Hou, J. - Robinson, H. - Ke, H.
Journal: J Med Chem

PDE9 inhibitors have been studied as therapeutics for treatment of cardiovascular diseases, diabetes, and neurodegenerative disorders. To illustrate the inhibitor selectivity, the crystal structures of the PDE9A catalytic domain in complex with the enantiomers of PDE9 inhibitor 1-(2-chlorophenyl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-d]py rimidine-4(5H)-one ((R)-BAY73-6691 or (S)-BAY73-6691, 1r or 1s) were determined and mutagenesis was performed. The structures showed that the fluoromethyl groups of 1r and 1s had different orientations while the other parts of the inhibitors commonly interacted with PDE9A. These differences may explain the slightly different affinity of 1r (IC(50) = 22 nM) and 1s (IC(50) = 88 nM). The mutagenesis experiments revealed that contribution of the binding residues to the inhibitor sensitivity varies dramatically, from few-fold to 3 orders of magnitude. On the basis of the crystal structures, a hypothesized compound that simulates the recently published PDE9 inhibitors was modeled to provide insight into the inhibitor selectivity.

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New structures and bioactivity properties of jasplakinolide (jaspamide) analogues from marine sponges.

Publication Date: 2010 Feb 25 PMID: 20121114
Authors: Robinson, S. J. - Morinaka, B. I. - Amagata, T. - Tenney, K. - Bray, W. M. - Gassner, N. C. - Lokey, R. S. - Crews, P.
Journal: J Med Chem

The goal of this study was to isolate and study additional jasplakinolide analogues from two taxonomically distinct marine sponges including two Auletta spp. and one Jaspis splendens. This led to the isolation of jasplakinolide (1) and eleven jasplakinolide analogues (3-13) including seven new analogues (6-10, 12, and 13). Structure elucidation of the new compounds was based on a combination of 1D and 2D NMR analysis, optical rotation, circular dichroism, and preparation of Mosher's esters. Five of the new compounds are oxidized tryptophan derivatives of 1, including a unique quinazoline derivative (9). Compounds 1, 3, 5-8, and 11 were evaluated in the NCI 60 cell line screen, and all compounds were tested in a microfilament disruption assay. Jasplakinolide B (11) exhibited potent cytotoxicity (GI(50) < 1 nM vs human colorectal adenocarcinoma (HCT-116) cells) but did not exhibit microfilament-disrupting activity at 80 nM.

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Synthesis, biological evaluation, and molecular modeling of 1-benzyl-1H-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2).

Publication Date: 2010 Feb 25 PMID: 20121113
Authors: Roumen, L. - Peeters, J. W. - Emmen, J. M. - Beugels, I. P. - Custers, E. M. - de Gooyer, M. - Plate, R. - Pieterse, K. - Hilbers, P. A. - Smits, J. F. - Vekemans, J. A. - Leysen, D. - Ottenheijm, H. C. - Janssen, H. M. - Hermans, J. J.
Journal: J Med Chem

Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved with mineralocorticoid receptor antagonists, however, aldosterone synthase (CYP11B2) inhibitors may offer a promising alternative. In this study, we used three-dimensional modeling of CYP11B2 to model the binding modes of the natural substrate 18-hydroxycorticosterone and the recently published CYP11B2 inhibitor R-fadrozole as a rational guide to design 44 structurally simple and achiral 1-benzyl-1H-imidazoles. Their syntheses, in vitro inhibitor potencies, and in silico docking are described. Some promising CYP11B2 inhibitors were identified, with our novel lead MOERAS115 (4-((5-phenyl-1H-imidazol-1-yl)methyl)benzonitrile) displaying an IC(50) for CYP11B2 of 1.7 nM, and a CYP11B2 (versus CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC(50) for CYP11B2 6.0 nM, selectivity 19.8). Molecular docking of the inhibitors in the models enabled us to generate posthoc hypotheses on their binding modes, providing a valuable basis for future studies and further design of CYP11B2 inhibitors.

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A novel cationic lipophosphoramide with diunsaturated lipid chains: synthesis, physicochemical properties, and transfection activities.

Publication Date: 2010 Feb 25 PMID: 20112994
Authors: Le Gall, T. - Loizeau, D. - Picquet, E. - Carmoy, N. - Yaouanc, J. J. - Burel-Deschamps, L. - Delepine, P. - Giamarchi, P. - Jaffres, P. A. - Lehn, P. - Montier, T.
Journal: J Med Chem

Cationic lipophosphoramidates constitute a class of cationic lipids we have previously reported to be efficient for gene transfection. Here, we synthesized and studied a novel lipophosphoramidate derivative characterized by an arsonium headgroup linked, via a phosphoramidate linker, to an unconventional lipidic moiety consisting of two diunsaturated linoleic chains. Physicochemical studies allowed us to comparatively evaluate the specific fluidity and fusogenicity properties of the liposomes formed. Although corresponding lipoplexes exhibited significant but relatively modest in vitro transfection efficiencies, they showed a remarkably efficient and reproducible ability to transfect mouse lung, with in vivo transfection levels higher than those observed with a monounsaturated analogue previously described. Thus, these results demonstrate that this diunsaturated cationic lipophosphoramidate constitutes an efficient and versatile nonviral vector for gene transfection. They also invite further evaluations of the transfection activity, especially in vivo, of gene delivery systems incorporating the lipid reported herein and/or other lipids bearing polyunsaturated chains.

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5-Modified-2'-dU and 2'-dC as mutagenic anti HIV-1 proliferation agents: synthesis and activity.

Publication Date: 2010 Feb 25 PMID: 20112915
Authors: El Safadi, Y. - Paillart, J. C. - Laumond, G. - Aubertin, A. M. - Burger, A. - Marquet, R. - Vivet-Boudou, V.
Journal: J Med Chem

With the goal of limiting HIV-1 proliferation by increasing the mutation rate of the viral genome, we synthesized a series of pyrimidine nucleoside analogues modified in position 5 of the aglycone moiety but unmodified on the sugar part. The synthetic strategies allow us to prepare the targeted compounds directly from commercially available nucleosides. All compounds were tested for their ability to reduce HIV-1 proliferation in cell culture. Two of them (5-hydroxymethyl-2'-dU (1c) and 5-hydroxymethyl-2'-dC (2c)) displayed a moderate antiviral activity in single passage experiments. The same two compounds plus two additional ones (5-carbamoyl-2'-dU (1a) and 5-carbamoylmethyl-2'-dU (1b)) were potent inhibitors of HIV-1 RT activity in serial passage assays, in which they induced a progressive loss of HIV-1 replication. In addition, viruses collected after seven passages in the presence of 1c and 2c replicated very poorly after withdrawal of these compounds, consistent with the accumulation of deleterious mutations in the HIV-1 genome.

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Studies of the synthesis of all stereoisomers of MG-132 proteasome inhibitors in the tumor targeting approach.

Publication Date: 2010 Feb 25 PMID: 20112914
Authors: Mroczkiewicz, M. - Winkler, K. - Nowis, D. - Placha, G. - Golab, J. - Ostaszewski, R.
Journal: J Med Chem

MG-132 is a tripeptide aldehyde (Z-l-leu-l-leu-l-leu-H, 2) proteasome inhibitor that exerts antitumor activity and enhances cytostatic/cytotoxic effects of chemo- and radiotherapy. Because of a troublesome synthesis of tripeptides with a non-natural configuration and modified side chains of amino acids, only two stereoisomers of MG-132 have been reported. Here, we propose a new approach to the synthesis of tripeptide aldehydes based on the Ugi reaction. Chiral, enantiomerically stable 2-isocyano-4-methylpentyl acetates were used as substrates for Ugi reaction resulting in a formation of tripeptide skeletons. Further functionalization of the obtained products led to a synthesis of tripeptide aldehydes. All stereoisomers of MG-132 were synthesized and studied as potential inhibitors of chymotrypsin-like, trypsin-like, and peptidylglutamyl peptide hydrolyzing activities of proteasome. These studies demonstrated the influence of absolute configuration of chiral aldehydes on the cytostatic/cytotoxic effects of the synthesized compounds and revealed that only (S,R,S)-(-)-2 stereoisomer is a more potent proteasome inhibitor than MG-132.

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Antisense oligonucleotides containing conformationally constrained 2',4'-(N-methoxy)aminomethylene and 2',4'-aminooxymethylene and 2'-O,4'-C-aminomethylene bridged nucleoside analogues show improved potency in animal models.

Publication Date: 2010 Feb 25 PMID: 20108935
Authors: Prakash, T. P. - Siwkowski, A. - Allerson, C. R. - Migawa, M. T. - Lee, S. - Gaus, H. J. - Black, C. - Seth, P. P. - Swayze, E. E. - Bhat, B.
Journal: J Med Chem

To identify chemistries and strategies to improve the potency of MOE second generation ASOs, we have evaluated gapmer antisense oligonucleotides containing BNAs having N-O bonds. These modifications include N-MeO-amino BNA, N-Me-aminooxy BNA, 2',4'-BNA(NC)[NMe], and 2',4'-BNA(NC) bridged nucleoside analogues. These modifications provided increased thermal stability and improved in vitro activity compared to the corresponding ASO containing the MOE modification. Additionally, ASOs containing N-MeO-amino BNA, N-Me-aminooxy BNA, and 2',4'-BNA(NC)[NMe] modifications showed improved in vivo activity (>5-fold) compared to MOE ASO. Importantly, toxicity parameters, such as AST, ALT, liver, kidney, and body weights, were found to be normal for N-MeO-amino BNA, N-Me-aminooxy BNA, and 2',4'-BNA(NC)[NMe] ASO treated animals. The data generated in these experiments suggest that N-MeO-amino BNA, N-Me-aminooxy BNA, and 2',4'-BNA(NC)[NMe] are useful modifications for applications in both antisense and other oligonucleotide based drug discovery efforts.

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New fluorinated 1,2,4-benzothiadiazine 1,1-dioxides: discovery of an orally active cognitive enhancer acting through potentiation of the 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors.

Publication Date: 2010 Feb 25 PMID: 20108934
Authors: Francotte, P. - Goffin, E. - Fraikin, P. - Lestage, P. - Van Heugen, J. C. - Gillotin, F. - Danober, L. - Thomas, J. Y. - Chiap, P. - Caignard, D. H. - Pirotte, B. - de Tullio, P.
Journal: J Med Chem

In the search of a potent cognitive enhancer, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as positive allosteric modulators of the AMPA receptors. In the present work, we focused our efforts on the insertion of mono- or polyfluoro-substituted alkyl chains at the 4-position of the thiadiazine ring in an attempt to enhance the pharmacokinetic behavior of previously described compounds. Among all the described compounds, 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, 12b, was shown to exert a strong activity on AMPA receptors in vitro and a marked cognitive-enhancing effect in vivo after oral administration to Wistar rats. Considering its in vivo activity, the metabolic degradation of 12b was studied and compared to that of its nonfluorinated analogue 9b. Taken together, results of this study clearly validated the positive impact of the fluorine atom on the alkyl chain at the 4-position of benzothiadiazine dioxides on activity and metabolic stability.

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Nitric oxide donors or nitrite counteract copper-[dithiocarbamate](2)-mediated tumor cell death and inducible nitric oxide synthase down-regulation: possible role of a nitrosyl-copper [dithiocarbamate](2) complex.

Publication Date: 2010 Feb 25 PMID: 20108933
Authors: Rhenals, M. V. - Strasberg-Rieber, M. - Rieber, M.
Journal: J Med Chem

In contrast to other metal-dithiocarbamate [DEDTC] complexes, the copper-DEDTC complex is highly cytotoxic, inducing oxidative stress, preferentially in tumor cells. Because nitric oxide (NO) forms adducts with Cu[DEDTC](2), we investigated whether NO donors like S-nitroso-N-acetyl penicillamine (SNAP) or sodium nitroprusside (SNP), and nitrite, a NO decomposition product, modulate Cu[DEDTC](2) cytotoxicity against human tumor cells. We show that apoptosis-associated PARP cleavage and inducible nitric oxide synthase (iNOS) down-regulation induced by nanomolar Cu[DEDTC](2), are counteracted by 50 muM SNAP, SNP, or CoCl(2), an inducer of hypoxia and NO signaling. Nitrite was stochiometrically effective in antagonizing Cu[DEDTC](2) cytotoxicity and inducing shifts in the absorption spectrum of the binary complex in the 280 and 450 nm regions. Subtoxic concentrations of Cu[DEDTC](2) became lethal when tumor cells were pretreated with c-PTIO, a membrane-impermeable scavenger for extracellular NO. Our results suggest that: (a) reactive oxygen species induced by Cu[DEDTC](2) are scavenged by nitrite released from NO, (b) the extent of lethality of Cu[DEDTC](2) is dependent on the reciprocal formation of an inactive ternary Cu[DEDTC](2)NO copper-nitrosyl complex.

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Synthesis of new thienyl ring containing HIV-1 protease inhibitors: promising preliminary pharmacological evaluation against recombinant HIV-1 proteases.

Publication Date: 2010 Feb 25 PMID: 20108932
Authors: Bonini, C. - Chiummiento, L. - De Bonis, M. - Di Blasio, N. - Funicello, M. - Lupattelli, P. - Pandolfo, R. - Tramutola, F. - Berti, F.
Journal: J Med Chem

A series of new thienyl ring containing analogues of nelfinavir and saquinavir with different substitution patterns were synthesized from suitable enantiopure diols. Their inhibitory activity against wild type recombinant HIV-1 protease was evaluated. In general thienyl groups spaced from the core by a methylene group gave products showing IC(50) in the nanomolar range, irrespective of the type and the substitution pattern of the heterocycle. The range of activity of the two most active compounds is substantially maintained or even increased against two commonly selected mutants, under drug pressure, such as V32I and V82A.

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Novel inhibitors of dengue virus methyltransferase: discovery by in vitro-driven virtual screening on a desktop computer grid.

Publication Date: 2010 Feb 25 PMID: 20108931
Authors: Podvinec, M. - Lim, S. P. - Schmidt, T. - Scarsi, M. - Wen, D. - Sonntag, L. S. - Sanschagrin, P. - Shenkin, P. S. - Schwede, T.
Journal: J Med Chem

Dengue fever is a viral disease that affects 50-100 million people annually and is one of the most important emerging infectious diseases in many areas of the world. Currently, neither specific drugs nor vaccines are available. Here, we report on the discovery of new inhibitors of the viral NS5 RNA methyltransferase, a promising flavivirus drug target. We have used a multistage molecular docking approach to screen a library of more than 5 million commercially available compounds against the two binding sites of this enzyme. In 263 compounds chosen for experimental verification, we found 10 inhibitors with IC(50) values of <100 microM, of which four exhibited IC(50) values of <10 microM in in vitro assays. The initial hit list also contained 25 nonspecific aggregators. We discuss why this likely occurred for this particular target. We also describe our attempts to use aggregation prediction to further guide the study, following this finding.

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Structure-activity relationships studies in a series of N,N-bis(alkanol)amine aryl esters as P-glycoprotein (Pgp) dependent multidrug resistance (MDR) inhibitors.

Publication Date: 2010 Feb 25 PMID: 20104851
Authors: Martelli, C. - Coronnello, M. - Dei, S. - Manetti, D. - Orlandi, F. - Scapecchi, S. - Novella Romanelli, M. - Salerno, M. - Mini, E. - Teodori, E.
Journal: J Med Chem

As a continuation of a previous research, a series of N,N-bis(alkanol)amine aryl esters, as Pgp-dependent MDR inhibitors, was designed and synthesized. The aromatic ester portions are suitably modulated, and new aryl rings (Ar(1) and Ar(2)) were combined with trans-3-(3,4,5-trimethoxyphenyl)vinyl, 3,4,5-trimethoxybenzyl and anthracene moieties that were present in the most potent previously studied compounds. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Selected compounds (5, 6, 8, 9, and 21) were further studied, evaluating their action on doxorubicin cytotoxicity potentiation on K562 cells; they significantly enhanced doxorubicin cytotoxicity on K562/DOX cells, confirming the results obtained with pirarubicin. Compound 9 shows the most promising properties as it was able to nearly completely reverse Pgp-dependent pirarubicin extrusion at nanomolar doses and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 19.1 at 3 microM dose.

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Subtlety of the structure-affinity and structure-efficacy relationships around a nonpeptide oxytocin receptor agonist.

Publication Date: 2010 Feb 25 PMID: 20104850
Authors: Frantz, M. C. - Rodrigo, J. - Boudier, L. - Durroux, T. - Mouillac, B. - Hibert, M.
Journal: J Med Chem

Very few nonpeptide oxytocin agonists have currently been reported, and none of them seem suitable for the in vivo investigation of the oxytocin mediated functions. In an attempt to rationalize the design of better tools, we have systematically studied the structural determinants of the affinity and efficacy of representative ligands of the V(1a), V(2), and OT receptor subtypes. Despite apparently obvious similarity between the ligand structures on one hand, and between the receptor subtypes on the other hand, the binding affinity and the functional activity profiles of truncated and hybrid ligands highlight the subtlety of ligand-receptor interactions for obtaining nonpeptide OT receptor agonists.

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Two-step synthesis of galactosylated human serum albumin as a targeted optical imaging agent for peritoneal carcinomatosis.

Publication Date: 2010 Feb 25 PMID: 20102220
Authors: Regino, C. A. - Ogawa, M. - Alford, R. - Wong, K. J. - Kosaka, N. - Williams, M. - Feild, B. J. - Takahashi, M. - Choyke, P. L. - Kobayashi, H.
Journal: J Med Chem

An optical probe, RG-(gal)(28)GSA, was synthesized to improve the detection of peritoneal implants by targeting the beta-d-galactose receptors highly expressed on the cell surface of a wide variety of cancers arising from the ovary, pancreas, colon, and stomach. Evaluation of RG-(gal)(28)GSA, RG-(gal)(20)GSA, glucose-analogue RG-(glu)(28)GSA, and control RG-HSA demonstrates specificity for the galactose, binding to several human adenocarcinoma cell lines, and cellular internalization. Studies using peritoneally disseminated SHIN3 xenografts in mice also confirmed a preference for galactose with the ability to detect submillimeter size lesions. Preliminary toxicity study for RG-(gal)(28)GSA using Balb/c mice reveal no toxic effects up to 100x of the standard imaging dose of 1 mg/kg administered either intraperitoneally or intravenously. These data indicate that RG-(gal)(28)GSA can selectively target a variety of human adenocarcinomas, can improve intraoperative or endoscopic tumor detection and resection, and may have little or no toxic in vivo effects; hence, it may be clinically translatable.

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Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na) as a potent antitumor agent.

Publication Date: 2010 Feb 25 PMID: 20102207
Authors: Chou, L. C. - Chen, C. T. - Lee, J. C. - Way, T. D. - Huang, C. H. - Huang, S. M. - Teng, C. M. - Yamori, T. - Wu, T. S. - Sun, C. M. - Chien, D. S. - Qian, K. - Morris-Natschke, S. L. - Lee, K. H. - Huang, L. J. - Kuo, S. C.
Journal: J Med Chem

CHM-1 [2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one] (1) has a unique antitumor mechanism of action. However, because 1 has relatively low hydrophilicity, it was evaluated only via ip administration, which is not clinically acceptable. In this study, we synthesized the monosodium phosphate salt (CHM-1-P-Na, 4) of 1 as a hydrophilic prodrug. Compound 4 was rapidly converted into 1 following iv and po administration and also possessed excellent antitumor activity in a SKOV-3 xenograft nude mice model. Compound 4 also had clear-cut pharmacological effects on enzymes related with tumor cells. Neither 4 nor 1 significantly affected normal biological function in a safety pharmacology profiling study. Compound 1 caused apoptotic effects in breast carcinoma cells via accumulation of cyclin B1, and importantly, the endogenous levels of the mitotic spindle checkpoint proteins BubR1 directly correlated with cellular response to microtubule disruption. With excellent antitumor activity profiles, 4 is highly promising for development as an anticancer clinical trials candidate.

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Discovery and clinical evaluation of 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-[2,2-difluo ro-2-phenylethylamino]pyrazinone (RWJ-671818), a thrombin inhibitor with an oxyguanidine P1 motif.

Publication Date: 2010 Feb 25 PMID: 20102150
Authors: Lu, T. - Markotan, T. - Ballentine, S. K. - Giardino, E. C. - Spurlino, J. - Brown, K. - Maryanoff, B. E. - Tomczuk, B. E. - Damiano, B. P. - Shukla, U. - End, D. - Andrade-Gordon, P. - Bone, R. F. - Player, M. R.
Journal: J Med Chem

We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.

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Characterization of tunable piperidine and piperazine carbamates as inhibitors of endocannabinoid hydrolases.

Publication Date: 2010 Feb 25 PMID: 20099888
Authors: Long, J. Z. - Jin, X. - Adibekian, A. - Li, W. - Cravatt, B. F.
Journal: J Med Chem

Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are two enzymes from the serine hydrolase superfamily that degrade the endocannabinoids 2-arachidonoylglycerol and anandamide, respectively. We have recently discovered that MAGL and FAAH are both inhibited by carbamates bearing an N-piperidine/piperazine group. Piperidine/piperazine carbamates show excellent in vivo activity, raising brain endocannabinoid levels and producing CB1-dependent behavioral effects in mice, suggesting that they represent a promising class of inhibitors for studying the endogenous functions of MAGL and FAAH. Herein, we disclose a full account of the syntheses, structure-activity relationships, and inhibitory activities of piperidine/piperazine carbamates against members of the serine hydrolase family. These scaffolds can be tuned for MAGL-selective or dual MAGL-FAAH inhibition by the attachment of an appropriately substituted bisarylcarbinol or aryloxybenzyl moiety, respectively, on the piperidine/piperazine ring. Modifications to the piperidine/piperazine ring ablated inhibitory activity, suggesting a strict requirement for a six-membered ring to maintain potency.

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Discovery and optimization of novel 3-piperazinylcoumarin antagonist of chemokine-like factor 1 with oral antiasthma activity in mice.

Publication Date: 2010 Feb 25 PMID: 20099827
Authors: Li, G. - Wang, D. - Sun, M. - Li, G. - Hu, J. - Zhang, Y. - Yuan, Y. - Ji, H. - Chen, N. - Liu, G.
Journal: J Med Chem

Chemokine-like factor 1 (CKLF1) is a novel functional cytokine that acts through its receptor CC chemokine receptor 4 (CCR4). Activation of CCR4 by CKLF1 plays an important role in diseases such as asthma and multiple sclerosis. This article describes a cell-based screening assay using an FITC-labeled CCR4 agonist (CKLF1-C27), a CKLF1 peptide fragment. Screening of our in-stock small-molecule library identified a 3-piperazinylcoumarin analogue 1 (IC(50) = 4.36 x 10(-6) M) that led to the discovery of orally active compound 41 (IC(50) = 2.12 x 10(-8) M) through systematic optimization. Compound 41 blocked the calcium mobilization and chemotaxis induced by CKLF1-C27 and reduced the asthmatic pathologic changes in lung tissue of human CKLF1-transfected mice. Further studies indicated that compound 41 ameliorated pathological changes via inhibition of the NF-kappaB signal pathway.

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Exploring epidermal growth factor receptor (EGFR) inhibitor features: the role of fused dioxygenated rings on the quinazoline scaffold.

Publication Date: 2010 Feb 25 PMID: 20095624
Authors: Chilin, A. - Conconi, M. T. - Marzaro, G. - Guiotto, A. - Urbani, L. - Tonus, F. - Parnigotto, P.
Journal: J Med Chem

A number of dioxolane, dioxane, and dioxepine quinazoline derivatives have been synthetized and evaluated as EGFR inhibitors. Their cytotoxic activity has been tested against two cell lines overexpressing and not expressing EGFR. Most derivatives were able to counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound PD153035. The size of the fused dioxygenated ring was crucial for the biological activity, the dioxane derivatives being the most promising class of this series.

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Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists.

Publication Date: 2010 Feb 25 PMID: 20095623
Authors: Katritch, V. - Jaakola, V. P. - Lane, J. R. - Lin, J. - Ijzerman, A. P. - Yeager, M. - Kufareva, I. - Stevens, R. C. - Abagyan, R.
Journal: J Med Chem

The recent progress in crystallography of G-protein coupled receptors opens an unprecedented venue for structure-based GPCR drug discovery. To test efficiency of the structure-based approach, we performed molecular docking and virtual ligand screening (VLS) of more than 4 million commercially available "drug-like" and ''lead-like'' compounds against the A(2A)AR 2.6 A resolution crystal structure. Out of 56 high ranking compounds tested in A(2A)AR binding assays, 23 showed affinities under 10 microM, 11 of those had sub-microM affinities and two compounds had affinities under 60 nM. The identified hits represent at least 9 different chemical scaffolds and are characterized by very high ligand efficiency (0.3-0.5 kcal/mol per heavy atom). Significant A(2A)AR antagonist activities were confirmed for 10 out of 13 ligands tested in functional assays. High success rate, novelty, and diversity of the chemical scaffolds and strong ligand efficiency of the A(2A)AR antagonists identified in this study suggest practical applicability of receptor-based VLS in GPCR drug discovery.

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Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates.

Publication Date: 2010 Feb 25 PMID: 20095622
Authors: Lundquist, J. T. - Harnish, D. C. - Kim, C. Y. - Mehlmann, J. F. - Unwalla, R. J. - Phipps, K. M. - Crawley, M. L. - Commons, T. - Green, D. M. - Xu, W. - Hum, W. T. - Eta, J. E. - Feingold, I. - Patel, V. - Evans, M. J. - Lai, K. - Borges-Marcucci, L. - Mahaney, P. E. - Wrobel, J. E.
Journal: J Med Chem

In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.

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Low molecular weight antagonists of the myelin-associated glycoprotein: synthesis, docking, and biological evaluation.

Publication Date: 2010 Feb 25 PMID: 20095613
Authors: Mesch, S. - Moser, D. - Strasser, D. S. - Kelm, A. - Cutting, B. - Rossato, G. - Vedani, A. - Koliwer-Brandl, H. - Wittwer, M. - Rabbani, S. - Schwardt, O. - Kelm, S. - Ernst, B.
Journal: J Med Chem

The injured adult mammalian central nervous system is an inhibitory environment for axon regeneration due to specific inhibitors, among them the myelin-associated glycoprotein (MAG), a member of the Siglec family (sialic-acid binding immunoglobulin-like lectin). In earlier studies, we identified the lead structure 5, which shows a 250-fold improved in vitro affinity for MAG compared to the tetrasaccharide binding epitope of GQ1balpha (1), the best physiological MAG ligand described so far. By modifying the 2- and 5-position, the affinity of 5 could be further improved to the nanomolar range (-->19a). Docking studies to a homology model of MAG allowed the rationalization of the experimental binding properties. Finally, pharmacokinetic parameters (stability in the cerebrospinal fluid, logD and permeation through the BBB) indicate the drug-like properties of the high-affinity antagonist 19a.

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5-OMe-UDP is a potent and selective P2Y(6)-receptor agonist.

Publication Date: 2010 Feb 25 PMID: 20095577
Authors: Ginsburg-Shmuel, T. - Haas, M. - Schumann, M. - Reiser, G. - Kalid, O. - Stern, N. - Fischer, B.
Journal: J Med Chem

P2Y nucleotide receptors (P2Y-Rs) play important physiological roles. However, most of the P2Y-R subtypes are still lacking potent and selective agonists and antagonists. Based on data mining analysis of binding interactions in 44 protein-uridine nucleos(t)ides complexes, we designed uracil nucleotides, substituted at the C5/C6 position. All C6-substituted derivatives were inactive at the P2Y(2,4,6)-Rs, while out of the C5-substituted analogues, only 5-OMe-UD(T)P showed activity. To rationalize the data, the ionization and conformation of these analogues were evaluated. The pK(a) values of most analogues substituted at the C5/C6 positions were unaltered compared to UTP (pK(a) 9.42), except for 5-F-UTP nucleotide (pK(a) 7.85). C6-substituted analogues adopt the syn or high-syn conformations, which are disfavored by the receptors, while 5-OMe-UD(T)P adopt the favored anti conformation. Furthermore, 5-OMe-UDP adopts the S sugar puckering, which is the conformation preferred by the P2Y(6)-R, but not the P2Y(2)- or P2Y(4)-Rs. 5-OMe-UDP fulfills the conformational and H-bonding requirements of P2Y(6)-R, thus, making a potent P2Y(6)-R agonist (EC(50) 0.08 microM), more than UDP (EC(50) 0.14 microM).

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Synthesis and structure-activity relationships of dimeric peptide antagonists of the human immunoglobulin G-human neonatal Fc receptor (IgG-FcRn) interaction.

Publication Date: 2010 Feb 25 PMID: 20092334
Authors: McDonnell, K. A. - Low, S. C. - Hoehn, T. - Donnelly, R. - Palmieri, H. - Fraley, C. - Sakorafas, P. - Mezo, A. R.
Journal: J Med Chem

The neonatal Fc receptor, FcRn, regulates the half-life of IgG in vivo and may be a target in the treatment of autoimmune disease. Monomeric peptide antagonists of the human IgG-human FcRn interaction were dimerized using three different synthetic methodologies: thiol/alkyl halide coupling of unprotected peptides, reductive alkylation of unprotected peptides, and on-resin amide bond formation with protected peptides. It was found that dimerization of monomeric peptides increased the in vitro activity of the peptide monomers more than 200-fold. Human IgG catabolism experiments in human FcRn transgenic mice were used to assess the in vivo activity of peptide dimers that possessed different linkers, cyclizations, and affinities for FcRn. Overall, it was found that the linker joining two monomeric peptides had only a minor effect on the in vitro potency but that in vitro potency was predictive of in vivo activity.

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Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.

Publication Date: 2010 Feb 25 PMID: 20092323
Authors: Gangjee, A. - Zaware, N. - Raghavan, S. - Ihnat, M. - Shenoy, S. - Kisliuk, R. L.
Journal: J Med Chem

Combinations of antiangiogenic agents (AAs) with cytotoxic agents have shown significant promise in cancer treatment, and several such clinical trials are currently underway. We have designed, synthesized, and evaluated two compounds that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor-beta (PDGFR-beta) for antiangiogenic effects and also inhibit human thymidylate synthase (hTS) for cytotoxic effects in single agents. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. The inhibitory potency of both these single agents against VEGFR-2, PDGFR-beta, and hTS is better than or close to standards. In a COLO-205 xenograft mouse model, one of the analogs significantly decreased tumor growth (tumor growth inhibition (TGI) = 76% at 35 mg/kg), liver metastases, and tumor blood vessels compared with a standard drug and with control and thus demonstrated potent tumor growth inhibition, inhibition of metastasis, and antiangiogenic effects in vivo. These compounds afford combination chemotherapeutic potential in single agents.

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Anti-influenza drug discovery: structure-activity relationship and mechanistic insight into novel angelicin derivatives.

Publication Date: 2010 Feb 25 PMID: 20092255
Authors: Yeh, J. Y. - Coumar, M. S. - Horng, J. T. - Shiao, H. Y. - Kuo, F. M. - Lee, H. L. - Chen, I. C. - Chang, C. W. - Tang, W. F. - Tseng, S. N. - Chen, C. J. - Shih, S. R. - Hsu, J. T. - Liao, C. C. - Chao, Y. S. - Hsieh, H. P.
Journal: J Med Chem

By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

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Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for chagas disease chemotherapy.

Publication Date: 2010 Feb 25 PMID: 20088534
Authors: Brak, K. - Kerr, I. D. - Barrett, K. T. - Fuchi, N. - Debnath, M. - Ang, K. - Engel, J. C. - McKerrow, J. H. - Doyle, P. S. - Brinen, L. S. - Ellman, J. A.
Journal: J Med Chem

A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogues in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.

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De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist.

Publication Date: 2010 Feb 25 PMID: 20088516
Authors: Nugiel, D. A. - Krumrine, J. R. - Hill, D. C. - Damewood, J. R. Jr - Bernstein, P. R. - Sobotka-Briner, C. D. - Liu, J. - Zacco, A. - Pierson, M. E.
Journal: J Med Chem

We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor.

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Substituted benzothiophene or benzofuran derivatives as a novel class of bone morphogenetic protein-2 up-regulators: synthesis, structure-activity relationships, and preventive bone loss efficacies in senescence accelerated mice (SAMP6) and ovariectomized rats.

Publication Date: 2010 Feb 25 PMID: 20088515
Authors: Guo, H. F. - Shao, H. Y. - Yang, Z. Y. - Xue, S. T. - Li, X. - Liu, Z. Y. - He, X. B. - Jiang, J. D. - Zhang, Y. Q. - Si, S. Y. - Li, Z. R.
Journal: J Med Chem

In this work, substituted benzothiophene and benzofuran compounds were found to be a new class of potential anabolic agents by enhancing BMP-2 expression. A series of benzothiophene and benzofuran derivatives have been synthesized, and their activities of up-regulating BMP-2 and bone loss prevention efficacies in SAMP6 mice and OVX rats have been studied. Benzothiophenes 1, 3, 14, 4a, 7a, 8a, and benzofuran analogue 2 showed higher BMP-2 up-regulation rates in vitro. Compound 8a was found to significantly affect the bone formation rate of tested SAMP6 mice. Compound 1 showed an improved bone quality in SAMP6 mice and also showed activity in OVX rats. We have demonstrated that substituted benzothiophene and benzofuran derivatives, especially compounds 1 and 8a, enhance BMP-2 expression in vitro and in vivo and stimulate bone formation and trabecular connectivity restoration in vivo. The compounds represent potential leads in the development of a new class of anabolic agents.

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Natural Product Chemistry for Drug Discovery (RSC Biomolecular Sciences No. 18) Natural Product Chemistry for Drug Discovery (RSC Biomolecular Sciences No. 18) . Edited by Antony D. Buss and Mark S.Butler. Royal Society of Chemistry , Cambridge, U.K. 2010 . xvii + 440 pp. 16 x 24 cm. ISBN 978-0-85404-193-0 . pound119.95.

Publication Date: 2010 Mar 11 PMID: 20088514
Authors: Kinghorn, A. D.
Journal: J Med Chem

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Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches.

Publication Date: 2010 Feb 25 PMID: 20088513
Authors: Rose, N. R. - Woon, E. C. - Kingham, G. L. - King, O. N. - Mecinovic, J. - Clifton, I. J. - Ng, S. S. - Talib-Hardy, J. - Oppermann, U. - McDonough, M. A. - Schofield, C. J.
Journal: J Med Chem

Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of N(epsilon)-methylated lysine residues in histones. Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. The results of initial binding and inhibition assays directed the production and analysis of a set of N-oxalyl-d-tyrosine derivatives to explore the extent of a subpocket at the JMJD2 active site. Some of the inhibitors were shown to be selective for JMJD2 over the hypoxia-inducible factor prolyl hydroxylase PHD2. A crystal structure of JMJD2A in complex with one of the potent inhibitors was obtained; modeling other inhibitors based on this structure predicts interactions that enable improved inhibition for some compounds.

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One step radiosynthesis of 6-[(18)F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester ([(18)F]F-Py-TFP): a new prosthetic group for efficient labeling of biomolecules with fluorine-18.

Publication Date: 2010 Feb 25 PMID: 20088512
Authors: Olberg, D. E. - Arukwe, J. M. - Grace, D. - Hjelstuen, O. K. - Solbakken, M. - Kindberg, G. M. - Cuthbertson, A.
Journal: J Med Chem

The labeling of biomolecules for positron emission tomography (PET) with no-carrier-added fluorine-18 is almost exclusively accomplished using prosthetic groups in a two step procedure. The inherent complexity of the process renders full automation a challenge and leads to protracted synthesis times. Here we describe a new (18)F-labeled prosthetic group based on nicotinic acid tetrafluorophenyl ester. Reaction of [(18)F]fluoride at 40 degrees C with the trimethylammonium precursor afforded 6-[(18)F]fluoronicotinic acid tetrafluorophenyl ester ([(18)F]F-Py-TFP) directly in 60-70% yield. [(18)F]F-Py-TFP was conveniently purified by Sep-Pak cartridge prior to incubation with a peptide containing the RGD sequence. The desired conjugate was formed rapidly and in good yields. An in vitro receptor-binding assay for the integrin alpha(v)beta(3) was established to explore competition with peptide and peptidomimetic prepared from F-Py-TFP with (125)I-echistatin. The nonradioactive conjugates were found to possess high binding affinities with calculated K(i) values in the low nanomolar range.

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Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry.

Publication Date: 2010 Feb 11 PMID: 20085328
Authors: Wang, L. - Cherian, C. - Desmoulin, S. K. - Polin, L. - Deng, Y. - Wu, J. - Hou, Z. - White, K. - Kushner, J. - Matherly, L. H. - Gangjee, A.
Journal: J Med Chem

2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl side chain and four to six carbon bridge lengths (compounds 1-3) were synthesized as substrates for folate receptors (FRs) and the proton-coupled folate transporter (PCFT). Conversion of acetylene carboxylic acids to alpha-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidines. Sonogashira coupling with (S)-2-[(5-bromo-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester, followed by hydrogenation and saponification, afforded 1-3. Compounds 1 and 2 potently inhibited KB and IGROV1 human tumor cells that express FR alpha, reduced folate carrier (RFC), and PCFT. The analogs were selective for FR and PCFT over RFC. Glycinamide ribonucleotide formyltransferase was the principal cellular target. In SCID mice with KB tumors, 1 was highly active against both early (3.5 log kill, 1/5 cures) and advanced (3.7 log kill, 4/5 complete remissions) stage tumors. Our results demonstrate potent in vitro and in vivo antitumor activity for 1 due to selective transport by FRs and PCFT over RFC.

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Chemical delivery system of metaiodobenzylguanidine (MIBG) to the central nervous system.

Publication Date: 2010 Feb 11 PMID: 20085326
Authors: Gourand, F. - Mercey, G. - Ibazizene, M. - Tirel, O. - Henry, J. - Levacher, V. - Perrio, C. - Barre, L.
Journal: J Med Chem

The aim of the present investigation was to apply a chemical delivery system (CDS) to MIBG (4) with the purpose of delivering this drug to the CNS. Compound 4 has been linked to a 1,4-dihydroquinoline moiety in order to achieve its CNS penetration, and here we report the synthesis to link 4 to the chemical delivery system and the radiosynthesis with carbon-11 of the "CDS-4 entity". After iv injection into rats of the [(11)C]CDS-4, the follow-up study of the radioactivity distribution in blood samples and brain homogenates and the analysis by HPLC and LC-MS/MS have confirmed the release of 4 into the CNS.

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Pyridinylquinoxalines and pyridinylpyridopyrazines as lead compounds for novel p38 alpha mitogen-activated protein kinase inhibitors.

Publication Date: 2010 Feb 11 PMID: 20078117
Authors: Koch, P. - Jahns, H. - Schattel, V. - Goettert, M. - Laufer, S.
Journal: J Med Chem

Various substituted 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines and 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)pyridopyrazines were synthesized as novel p38 alpha MAP kinase inhibitors via different short synthetic strategies with high variation possibilities. The formation of the quinoxaline/pyridopyrazine core was achieved from alpha-diketones and o-phenylenediamines/alpha-diaminopyridines under microwave irradiation. Introduction of an amino moiety at the pyridine C2 position of the 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines led to compounds showing potent enzyme inhibition down to the double-digit nanomolar range (6f; IC(50) = 81 nM). Replacement of the quinoxaline core with pyrido[2,3-b]pyrazine gave compound 9e with superior p38 alpha MAP kinase inhibition (IC(50) = 38 nM).

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Benzimidazole derivatives as new serotonin 5-HT6 receptor antagonists. Molecular mechanisms of receptor inactivation.

Publication Date: 2010 Feb 11 PMID: 20078106
Authors: de la Fuente, T. - Martin-Fontecha, M. - Sallander, J. - Benhamu, B. - Campillo, M. - Medina, R. A. - Pellissier, L. P. - Claeysen, S. - Dumuis, A. - Pardo, L. - Lopez-Rodriguez, M. L.
Journal: J Med Chem

On the basis of our previously described pharmacophore model for serotonin 5-HT(6) receptor (5-HT(6)R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1-20 that represent a new family of potent antagonists at the human 5-HT(6)R. Site-directed mutagenesis and a beta(2)-adrenoceptor-based homology model of the 5-HT(6)R were used to predict the mode of binding of antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH(2)-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT(6)R antagonists.

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Multifunctional antioxidants for the treatment of age-related diseases.

Publication Date: 2010 Feb 11 PMID: 20078105
Authors: Jin, H. - Randazzo, J. - Zhang, P. - Kador, P. F.
Journal: J Med Chem

Analogues of N,N-dimethyl-4-(pyrimidin-2-yl)piperazine-1-sulfonamide possessing a free radical scavenger group (FRS), chelating groups (CHL), or both (FRS + CHL) have been synthesized. Electrospray ionization mass spectrometry studies indicate that select members of this series bind ions in the relative order of Cu(1+) = Cu(2+) > Fe(2+) = Fe(3+) > Zn(2+) with no binding of Ca(2+) or Mg(2+) observed. In vitro evaluation of these compounds in human lens epithelial, human retinal pigmented epithelial, and human hippocampal astrocyte cell lines indicates that all analogues possessing the FRS group as well as the water-soluble vitamin E analogue 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid protect these cells against decreased cell viability and glutathione levels induced by hydrogen peroxide. In addition, those compounds possessing CHL groups also protected these cells against hydroxyl radicals generated by the Fenton reaction. These compounds are good candidates for the preventive treatment of cataract, age-related macular degeneration (AMD), and Alzheimer's dementia (AD).

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Design, synthesis, and docking studies of novel benzimidazoles for the treatment of metabolic syndrome.

Publication Date: 2010 Feb 11 PMID: 20073471
Authors: Mizuno, C. S. - Chittiboyina, A. G. - Shah, F. H. - Patny, A. - Kurtz, T. W. - Pershadsingh, H. A. - Speth, R. C. - Karamyan, V. T. - Carvalho, P. B. - Avery, M. A.
Journal: J Med Chem

In addition to lowering blood pressure, telmisartan, an angiotensin (AT(1)) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPAR gamma active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPAR gamma agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT(1) receptor with a K(i) = 13.4 nM, but it was devoid of PPAR gamma activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPAR gamma transactivation assay (69% activation) with no affinity for the AT(1) receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARgamma activity (29%) and affinity for the AT(1) receptor (K(i) = 2.5 microM).

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Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination.

Publication Date: 2010 Feb 11 PMID: 20070106
Authors: Varma, M. V. - Obach, R. S. - Rotter, C. - Miller, H. R. - Chang, G. - Steyn, S. J. - El-Kattan, A. - Troutman, M. D.
Journal: J Med Chem

Oral bioavailability (F) is a product of fraction absorbed (Fa), fraction escaping gut-wall elimination (Fg), and fraction escaping hepatic elimination (Fh). In this study, using a database comprised of Fa, Fg, Fh, and F values for 309 drugs in humans, an analysis of the interrelation of physicochemical properties and the individual parameters was carried out in order to define the physicochemical space for optimum human oral bioavailability. Trend analysis clearly indicated molecular weight (MW), ionization state, lipophilicity, polar descriptors, and free rotatable bonds (RB) influence bioavailability. These trends were due to a combination of effects of the properties on Fa and first-pass elimination (Fg and Fh). Higher MW significantly impacted Fa, while Fg and Fh decreased with increasing lipophilicity. Parabolic trends were observed for bioavailability with polar descriptors. Interestingly, RB has a negative effect on all three parameters, leading to its pronounced effect on bioavailability. In conclusion, physicochemical properties influence bioavailability with typically opposing effects on Fa and first-pass elimination. This analysis may provide a rational judgment on the physicochemical space to optimize oral bioavailability.

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Structure-function relationships and crystal structures of the vitamin D receptor bound 2 alpha-methyl-(20S,23S)- and 2 alpha-methyl-(20S,23R)-epoxymethano-1 alpha,25-dihydroxyvitamin D3.

Publication Date: 2010 Feb 11 PMID: 20070104
Authors: Antony, P. - Sigueiro, R. - Huet, T. - Sato, Y. - Ramalanjaona, N. - Rodrigues, L. C. - Mourino, A. - Moras, D. - Rochel, N.
Journal: J Med Chem

The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (2a) acts as a 1 alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D(3), 2 alpha-methyl-1 alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.

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Design and synthesis of novel quinone inhibitors targeted to the redox function of apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (Ape1/ref-1).

Publication Date: 2010 Feb 11 PMID: 20067291
Authors: Nyland, R. L. - Luo, M. - Kelley, M. R. - Borch, R. F.
Journal: J Med Chem

The multifunctional enzyme apurinic endonuclease 1/redox enhancing factor 1 (Ape1/ref-1) maintains genetic fidelity through the repair of apurinic sites and regulates transcription through redox-dependent activation of transcription factors. Ape1 can therefore serve as a therapeutic target in either a DNA repair or transcriptional context. Inhibitors of the redox function can be used as either therapeutics or novel tools for separating the two functions for in vitro study. Presently there exist only a few compounds that have been reported to inhibit Ape1 redox activity; here we describe a series of quinones that exhibit micromolar inhibition of the redox function of Ape1. Benzoquinone and naphthoquinone analogues of the Ape1-inhibitor E3330 were designed and synthesized to explore structural effects on redox function and inhibition of cell growth. Most of the naphthoquinones were low micromolar inhibitors of Ape1 redox activity, and the most potent analogues inhibited tumor cell growth with IC(50) values in the 10-20 microM range.

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Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor.

Publication Date: 2010 Feb 11 PMID: 20067290
Authors: Carolan, C. G. - Dillon, G. P. - Khan, D. - Ryder, S. A. - Gaynor, J. M. - Reidy, S. - Marquez, J. F. - Jones, M. - Holland, V. - Gilmer, J. F.
Journal: J Med Chem

Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.

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Synthesis and biological evaluation of new podophyllic aldehyde derivatives with cytotoxic and apoptosis-inducing activities.

Publication Date: 2010 Feb 11 PMID: 20067289
Authors: Castro, M. A. - del Corral, J. M. - Garcia, P. A. - Rojo, M. V. - de la Iglesia-Vicente, J. - Mollinedo, F. - Cuevas, C. - San Feliciano, A.
Journal: J Med Chem

Several series of nonlactonic podophyllic aldehyde analogues were prepared and evaluated against several human tumor cell lines. They had different combinations of aldehyde, imine, amine, ester, and amide functions at C-9 and C-9' of the cyclolignan skeleton. All the compounds synthesized showed cytotoxicity levels in the microM range and below. Within the new series tested, compounds having an aldehyde or imine at C-9 and an ester at C-9' were the most potent, with GI(50) values in the nM range, some of them being several times more potent against HT-29 and A-549 carcinoma than against MB-231 melanoma cells. Cell cycle studies and analysis of the microtubule-disrupting capacity have demonstrated the existence of two different mechanisms of cell death induction for compounds with closely related structures.

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Structural discovery of small molecule binding sites in Cu-Zn human superoxide dismutase familial amyotrophic lateral sclerosis mutants provides insights for lead optimization.

Publication Date: 2010 Feb 11 PMID: 20067275
Authors: Antonyuk, S. - Strange, R. W. - Hasnain, S. S.
Journal: J Med Chem

Dominant inheritance of point mutations in CuZn superoxide dismutase (SOD1) is the best characterized subset of familial amyotrophic lateral sclerosis (FALS) and accounts for some 20% of the known familial cases. We report the discovery and visualization via cocrystallography of two ligand-binding pockets in human SOD1 and its pathogenic mutants that have opened up the real possibility of undertaking lead compound discovery using a fragment-based approach for therapeutic purposes for SOD1 associated motor neuron disease.

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Transforming rhinacanthin analogues from potent anticancer agents into potent antimalarial agents.

Publication Date: 2010 Feb 11 PMID: 20067272
Authors: Kongkathip, N. - Pradidphol, N. - Hasitapan, K. - Grigg, R. - Kao, W. C. - Hunte, C. - Fisher, N. - Warman, A. J. - Biagini, G. A. - Kongsaeree, P. - Chuawong, P. - Kongkathip, B.
Journal: J Med Chem

Twenty-six novel naphthoquinone aliphatic esters were synthesized by esterification of 1,4-naphthoquinone alcohols with various aliphatic acids. The 1,4-naphthoquinone alcohols were prepared from 1-hydroxy-2-naphthoic acid in nine steps with excellent yields. Twenty-four of the novel synthetic naphthoquinone esters showed significant antimalarial activity with IC(50) values in the range of 0.03-16.63 microM. The length of the aliphatic chain and the presence of C-2' substituents on the propyl chain affected the activity. Interestingly, compounds 31 and 37 showed very good antimalarial activity and were not toxic to normal Vero cells, and the PTI values of 31 (>1990.38) and 37 (1825.94) are excellent. Both 31 and 37 showed potent inhibition against P. falciparum 3D7 cyt bc(1) and no inhibition on rat cyt bc(1). They showed IC(50) values in the nanomolar range, providing full inhibition of cyt bc(1) with one molecule inhibitor bound per cyt bc(1) monomer at the Q(o) site.

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Novel highly potent and selective sigma 1 receptor antagonists related to spipethiane.

Publication Date: 2010 Feb 11 PMID: 20067271
Authors: Piergentili, A. - Amantini, C. - Del Bello, F. - Giannella, M. - Mattioli, L. - Palmery, M. - Perfumi, M. - Pigini, M. - Santoni, G. - Tucci, P. - Zotti, M. - Quaglia, W.
Journal: J Med Chem

Conservative chemical modifications of the core structure of the lead spipethiane (1) afforded novel potent sigma(1) ligands. sigma(1) affinity and sigma(1/)sigma(2) selectivity proved to be favored by the introduction of polar functions (oxygen atom or carbonyl group) in position 3 or 4 (4-6) or by the elongation of the distance between the two hydrophobic portions of the molecule with the simultaneous presence of a carbonyl group in position 4 (8 and 9). The observed cytostatic effect against the human breast cancer cell line MCF-7/ADR, highly expressing sigma(1) receptors, and not against MCF-7, as well as the enhancement of morphine analgesia highlighted the sigma(1) antagonist profile of this series of compounds. In particular, due to its high sigma(1) affinity (pK(i) = 10.28) and sigma(1)/sigma(2) selectivity ratio (29510), compound 9 might be a novel valuable tool for sigma receptor characterization and a suitable template for the rational design of potential therapeutically useful sigma(1) antagonists.

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Structure-activity studies of urea, carbamate, and sulfonamide derivatives of acylfulvene.

Publication Date: 2010 Feb 11 PMID: 20067264
Authors: McMorris, T. C. - Chimmani, R. - Alisala, K. - Staake, M. D. - Banda, G. - Kelner, M. J.
Journal: J Med Chem

Illudin S and M (1, 2) are highly toxic sesquiterpenes found in the basidiomycete Omphalotus illudens. Illudins have a low therapeutic index, but acylfulvene derivatives display potent in vivo antitumor activity against a variety of multidrug resistant tumors. The lead acylfulvene (4), irofulven (5), in a randomized phase IIB clinical trial significantly increased overall survival in patients with metastatic hormone-refractory prostate cancer who failed prior treatment with two different standard chemotherapeutic regimens. Irofulven is unique, as the primary allylic hydroxyl group can undergo displacement with a variety of nucleophiles to produce analogues that retain key functional groups required for biological activity including the reactive cyclopropylmethyl carbinol and alpha,beta-unsaturated ketone. As described here, we synthesized a variety of urea, carbamate, and sulfonamide derivatives that retain key functional groups and display potent biological activity toward target solid tumor cells in vitro but are relatively nontoxic toward a nontarget B-cell derived cell line.

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A series of alpha-amino acid ester prodrugs of camptothecin: in vitro hydrolysis and A549 human lung carcinoma cell cytotoxicity.

Publication Date: 2010 Feb 11 PMID: 20063889
Authors: Deshmukh, M. - Chao, P. - Kutscher, H. L. - Gao, D. - Sinko, P. J.
Journal: J Med Chem

The objective of the present study was to identify a camptothecin (CPT) prodrug with optimal release and cytotoxicity properties for immobilization on a passively targeted microparticle delivery system. A series of alpha-amino acid ester prodrugs of CPT were synthesized, characterized, and evaluated. Four CPT prodrugs were synthesized with increasing aliphatic chain length (glycine (Gly) (2a), alanine (Ala) (2b), aminobutyric acid (Abu) (2c), and norvaline (Nva) (2d)). Prodrug reconversion was studied at pH 6.6, 7.0, and 7.4 corresponding to tumor, lung, and extracellular/physiological pH, respectively. Cytotoxicity was evaluated in A549 human lung carcinoma cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The hydrolytic reconversion rate to parent CPT increased with decreasing side chain length as well as increasing pH. The Hill slope of 2d was significantly less than CPT and the other prodrugs tested, indicating a higher cell death rate at lower concentrations. These results suggest that 2d is the best candidate for a passively targeted sustained release lung delivery system.

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Rational design of indoleamine 2,3-dioxygenase inhibitors.

Publication Date: 2010 Feb 11 PMID: 20055453
Authors: Rohrig, U. F. - Awad, L. - Grosdidier, A. - Larrieu, P. - Stroobant, V. - Colau, D. - Cerundolo, V. - Simpson, A. J. - Vogel, P. - Van den Eynde, B. J. - Zoete, V. - Michielin, O.
Journal: J Med Chem

Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We have used the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. First, we investigated the modes of binding of all known IDO inhibitors. On the basis of the observed docked conformations, we developed a pharmacophore model, which was then used to devise new compounds to be tested for IDO inhibition. We also used a fragment-based approach to design and to optimize small organic molecule inhibitors. Both approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.

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Synthesis and biological evaluation of triazol-4-ylphenyl-bearing histone deacetylase inhibitors as anticancer agents.

Publication Date: 2010 Feb 11 PMID: 20055418
Authors: He, R. - Chen, Y. - Chen, Y. - Ougolkov, A. V. - Zhang, J. S. - Savoy, D. N. - Billadeau, D. D. - Kozikowski, A. P.
Journal: J Med Chem

Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide[3-(1-phenyl-1H-[1,2,3]triazol-4-yl)phenyl]amide (4a), suppresses pancreatic cancer cell growth in vitro with the lowest IC(50) value of 20 nM against MiaPaca-2 cell. In this study, we continued our efforts to develop triazol-4-ylphenyl bearing hydroxamate analogues by embellishing the terminal phenyl ring of 4a with different substituents. The isoform inhibitory profile of these hydroxamate analogues was similar to those of 4a. All of these triazol-4-ylphenyl bearing hydroxamates are pan-HDACIs like SAHA. Moreover, compounds 4h and 11a were found to be very effective inhibitors of cancer cell growth in the HupT3 (IC(50) = 50 nM) and MiaPaca-2 (IC(50) = 40 nM) cancer cell lines, respectively. Compound 4a was found to reactivate the expression of CDK inhibitor proteins and to suppress pancreatic cancer cell growth in vivo. Taken together, these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies.

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Synthesis and opioid activity of enantiomeric N-substituted 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolines.

Publication Date: 2010 Feb 11 PMID: 20055417
Authors: Hsin, L. W. - Chang, L. T. - Rothman, R. B. - Dersch, C. M. - Fishback, J. A. - Matsumoto, R. R.
Journal: J Med Chem

A series of enantiomeric N-substituted 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolines was synthesized. The (-)-enantiomers had much greater kappa-, mu-, and delta-opioid receptor binding affinity than the corresponding (+)-enantiomers. Compounds (-)-1a, (-)-1b, and (-)-1c displayed subnanomolar binding affinity for the mu-receptor, and (-)-1b had a high affinity for the kappa-receptor. Compound (-)-1a was a mu-partial agonist and kappa-antagonist. Compound (-)-1b was a potent neutral mu-antagonist (K(d) = 0.22 nM) and a kappa-partial agonist.

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Novel oxadiazole analogues derived from ethacrynic acid: design, synthesis, and structure-activity relationships in inhibiting the activity of glutathione S-transferase P1-1 and cancer cell proliferation.

Publication Date: 2010 Feb 11 PMID: 20055416
Authors: Yang, X. - Liu, G. - Li, H. - Zhang, Y. - Song, D. - Li, C. - Wang, R. - Liu, B. - Liang, W. - Jing, Y. - Zhao, G.
Journal: J Med Chem

Ethacrynic acid (EA) is a glutathione S-transferase P1-1 (GST P1-1) inhibitor with weak antiproliferative ability in tumor cells. By use of the principle of bioisosterism, a series of novel EA oxadiazole analogues were designed and synthesized. The structure-activity relationships of inhibiting GST P1-1 activity and cell proliferation of those EA analogues were investigated in human leukemia HL-60 cells. Our data revealed that those EA oxadiazole analogues had improved antiproliferative activity and most of them had similar or better inhibitory effects on GST P1-1 activity than EA. Compound 6u was one of the potent antiproliferative agents without inhibition of GST P1-1 activity. Compounds 6r and 6s were two potent cell growth inhibitors in several solid tumor cell lines with the concentrations inhibiting half of cell growth of less than 5 microM. Our data suggest that these EA oxadiazole analogues are promising antitumor agents that may act through GST P1-1 inhibition-dependent and/or -independent pathways.

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Highly suppressing wild-type HIV-1 and Y181C mutant HIV-1 strains by 10-chloromethyl-11-demethyl-12-oxo-calanolide A with druggable profile.

Publication Date: 2010 Feb 11 PMID: 20050672
Authors: Xue, H. - Lu, X. - Zheng, P. - Liu, L. - Han, C. - Hu, J. - Liu, Z. - Ma, T. - Li, Y. - Wang, L. - Chen, Z. - Liu, G.
Journal: J Med Chem

We herein report a new compound: 10-chloromethyl-11-demethyl-12-oxo-calanolide A (20, EC(50) = 7.4 nM, SI = 1417), which demonstrates a druggable profile with 32.7% oral bioavailability in rat, tolerated oral single dose toxicity in mice, and especially the feature of highly efficient suppression of the wild-type HIV-1 and Y181C mutant HIV-1 at an EC(50) = 7.4 nM and EC(50) = 0.46 nM, respectively.

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Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer.

Publication Date: 2010 Feb 11 PMID: 20050669
Authors: Sutherlin, D. P. - Sampath, D. - Berry, M. - Castanedo, G. - Chang, Z. - Chuckowree, I. - Dotson, J. - Folkes, A. - Friedman, L. - Goldsmith, R. - Heffron, T. - Lee, L. - Lesnick, J. - Lewis, C. - Mathieu, S. - Nonomiya, J. - Olivero, A. - Pang, J. - Prior, W. W. - Salphati, L. - Sideris, S. - Tian, Q. - Tsui, V. - Wan, N. C. - Wang, S. - Wiesmann, C. - Wong, S. - Zhu, B. Y.
Journal: J Med Chem

The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.

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Cationic amphiphile with shikimic acid headgroup shows more systemic promise than its mannosyl analogue as DNA vaccine carrier in dendritic cell based genetic immunization.

Publication Date: 2010 Feb 11 PMID: 20050668
Authors: Srinivas, R. - Karmali, P. P. - Pramanik, D. - Garu, A. - Mahidhar, Y. V. - Majeti, B. K. - Ramakrishna, S. - Srinivas, G. - Chaudhuri, A.
Journal: J Med Chem

Mannosylated cationic vectors have been previously used for delivering DNA vaccines to antigen presenting cells (APCs) via mannose receptors expressed on the cell surface of APCs. Here we show that cationic amphiphiles containing mannose-mimicking quinic acid and shikimic acid headgroups deliver genes to APCs via mannose receptor. Cationic amphiphile with shikimic acid headgroup was more efficacious than its mannosyl counterpart in combating mouse tumor growth by dendritic cell (the most professional APC) based genetic immunization.

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Design, synthesis, biological properties, and molecular modeling investigations of novel tacrine derivatives with a combination of acetylcholinesterase inhibition and cannabinoid CB1 receptor antagonism.

Publication Date: 2010 Feb 11 PMID: 20047331
Authors: Lange, J. H. - Coolen, H. K. - van der Neut, M. A. - Borst, A. J. - Stork, B. - Verveer, P. C. - Kruse, C. G.
Journal: J Med Chem

Pyrazolines 7-10 were designed as novel CB(1) receptor antagonists, which exhibited improved turbidimetric aqueous solubilities. On the basis of their extended CB(1) antagonist pharmacophore, hybrid molecules exhibiting cannabinoid CB(1) receptor antagonistic as well as acetylcholinesterase (AChE) inhibiting activities were designed. The target compounds 12, 13, 20, and 21 are based on 1 (tacrine) as the AChE inhibitor (AChEI) pharmacophore and two different CB(1) antagonistic pharmacophores. The imidazole-based 20 showed high CB(1) receptor affinity (48 nM) in combination with high CB(1)/CB(2) receptor subtype selectivity (>20-fold) and elicited equipotent AChE inhibitory activity as 1. Molecular modeling studies revealed the presence of a binding pocket in the AChE enzyme which nicely accommodates the CB(1) pharmacophores of the target compounds 12, 13, 20, and 21.

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Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: application to the synthesis of glucocorticoid receptor modulators.

Publication Date: 2010 Feb 11 PMID: 20047280
Authors: Xiao, H. Y. - Wu, D. R. - Malley, M. F. - Gougoutas, J. Z. - Habte, S. F. - Cunningham, M. D. - Somerville, J. E. - Dodd, J. H. - Barrish, J. C. - Nadler, S. G. - Dhar, T. G.
Journal: J Med Chem

The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring. More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.

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2,4,6-trisubstituted triazines as protein a mimetics for the treatment of autoimmune diseases.

Publication Date: 2010 Feb 11 PMID: 20047277
Authors: Zacharie, B. - Abbott, S. D. - Bienvenu, J. F. - Cameron, A. D. - Cloutier, J. - Duceppe, J. S. - Ezzitouni, A. - Fortin, D. - Houde, K. - Lauzon, C. - Moreau, N. - Perron, V. - Wilb, N. - Asselin, M. - Doucet, A. - Fafard, M. E. - Gaudreau, D. - Grouix, B. - Sarra-Bournet, F. - St-Amant, N. - Gagnon, L. - Penney, C. L.
Journal: J Med Chem

A first-in-class series of low molecular weight trisubstituted triazines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure-activity relationship (SAR) demonstrates that the 1,3-phenylenediamine component was essential for robust activity. Twenty-two compounds, represented by lead molecule 34, displayed significant activity compared to protein A. These compounds may prove useful for the treatment of autoimmune disease.

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Antitrypanosomal activity of 1,2-dihydroquinolin-6-ols and their ester derivatives.

Publication Date: 2010 Feb 11 PMID: 20047276
Authors: Fotie, J. - Kaiser, M. - Delfin, D. A. - Manley, J. - Reid, C. S. - Paris, J. M. - Wenzler, T. - Maes, L. - Mahasenan, K. V. - Li, C. - Werbovetz, K. A.
Journal: J Med Chem

The current chemotherapy for second stage human African trypanosomiasis is unsatisfactory. A synthetic optimization study based on the lead antitrypanosomal compound 1,2-dihydro-2,2,4-trimethylquinolin-6-yl 3,5-dimethoxybenzoate (TDR20364, 1a) was undertaken in an attempt to discover new trypanocides with potent in vivo activity. While 6-ether derivatives were less active than the lead compound, several N1-substituted derivatives displayed nanomolar IC(50) values against T. b. rhodesiense STIB900 in vitro, with selectivity indexes up to >18000. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate (10a) displayed an IC(50) value of 0.014 microM against these parasites and a selectivity index of 1700. Intraperitoneal administration of 10a at 50 (mg/kg)/day for 4 days caused a promising prolongation of lifespan in T. b. brucei STIB795-infected mice (>14 days vs 7.75 days for untreated controls). Reactive oxygen species were produced when T. b. brucei were exposed to 10a in vitro, implicating oxidative stress in the trypanocidal mode of action of these 1,2-dihydroquinoline derivatives.

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Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors.

Publication Date: 2010 Feb 11 PMID: 20043700
Authors: Wang, Y. S. - Strickland, C. - Voigt, J. H. - Kennedy, M. E. - Beyer, B. M. - Senior, M. M. - Smith, E. M. - Nechuta, T. L. - Madison, V. S. - Czarniecki, M. - McKittrick, B. A. - Stamford, A. W. - Parker, E. M. - Hunter, J. C. - Greenlee, W. J. - Wyss, D. F.
Journal: J Med Chem

Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper

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Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I--inhibitor design and validation.

Publication Date: 2010 Feb 11 PMID: 20043696
Authors: Zhu, Z. - Sun, Z. Y. - Ye, Y. - Voigt, J. - Strickland, C. - Smith, E. M. - Cumming, J. - Wang, L. - Wong, J. - Wang, Y. S. - Wyss, D. F. - Chen, X. - Kuvelkar, R. - Kennedy, M. E. - Favreau, L. - Parker, E. - McKittrick, B. A. - Stamford, A. - Czarniecki, M. - Greenlee, W. - Hunter, J. C.
Journal: J Med Chem

A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.

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Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models.

Publication Date: 2010 Feb 11 PMID: 20043678
Authors: O'Donnell, C. J. - Rogers, B. N. - Bronk, B. S. - Bryce, D. K. - Coe, J. W. - Cook, K. K. - Duplantier, A. J. - Evrard, E. - Hajos, M. - Hoffmann, W. E. - Hurst, R. S. - Maklad, N. - Mather, R. J. - McLean, S. - Nedza, F. M. - O'Neill, B. T. - Peng, L. - Qian, W. - Rottas, M. M. - Sands, S. B. - Schmidt, A. W. - Shrikhande, A. V. - Spracklin, D. K. - Wong, D. F. - Zhang, A. - Zhang, L.
Journal: J Med Chem

A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.

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Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication.

Publication Date: 2010 Feb 11 PMID: 20043638
Authors: Bridger, G. J. - Skerlj, R. T. - Hernandez-Abad, P. E. - Bogucki, D. E. - Wang, Z. - Zhou, Y. - Nan, S. - Boehringer, E. M. - Wilson, T. - Crawford, J. - Metz, M. - Hatse, S. - Princen, K. - De Clercq, E. - Schols, D.
Journal: J Med Chem

Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC(50)'s against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC(50) against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration.

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Synthesis and anticonvulsant activities of (R)-N-(4'-substituted)benzyl 2-acetamido-3-methoxypropionamides.

Publication Date: 2010 Feb 11 PMID: 20041718
Authors: Salome, C. - Salome-Grosjean, E. - Park, K. D. - Morieux, P. - Swendiman, R. - DeMarco, E. - Stables, J. P. - Kohn, H.
Journal: J Med Chem

The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide [(R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-3] has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2', 3', 4') showed that 4'-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4'-site. The SAR indicated that nonbulky 4'-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were comparable with or exceeded that of (R)-3 and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate.

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Characterization of sirtuin inhibitors in nematodes expressing a muscular dystrophy protein reveals muscle cell and behavioral protection by specific sirtinol analogues.

Publication Date: 2010 Feb 11 PMID: 20041717
Authors: Pasco, M. Y. - Rotili, D. - Altucci, L. - Farina, F. - Rouleau, G. A. - Mai, A. - Neri, C.
Journal: J Med Chem

In oculopharyngeal muscular dystrophy (OPMD), a disease caused by polyalanine expansion in the nuclear protein PABPN1, the genetic inhibition of sirtuins and treatment with sirtuin inhibitors protect from mutant PABPN1 toxicity in transgenic nematodes. Here, we tested the SIRT1/2 inhibitors 1-12, bearing different degrees of inhibition, for protection against mutant PABPN1 toxicity in Caenorhabditis elegans. Compounds 2, 4, and 11 were the most efficient, revealing a potential therapeutic application for muscle cell protection in OPMD.

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Conjugates of desferrioxamine B (DFOB) with derivatives of adamantane or with orally available chelators as potential agents for treating iron overload.

Publication Date: 2010 Feb 11 PMID: 20041672
Authors: Liu, J. - Obando, D. - Schipanski, L. G. - Groebler, L. K. - Witting, P. K. - Kalinowski, D. S. - Richardson, D. R. - Codd, R.
Journal: J Med Chem

Desferrioxamine B (DFOB) conjugates with adamantane-1-carboxylic acid, 3-hydroxyadamantane-1-carboxylic acid, 3,5-dimethyladamantane-1-carboxylic acid, adamantane-1-acetic acid, 4-methylphenoxyacetic acid, 3-hydroxy-2-methyl-4-oxo-1-pyridineacetic acid (N-acetic acid derivative of deferiprone), or 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox) were prepared and the integrity of Fe(III) binding of the compounds was established from electrospray ionization mass spectrometry and RP-HPLC measurements. The extent of intracellular (59)Fe mobilized by the DFOB-3,5-dimethyladamantane-1-carboxylic acid adduct was 3-fold greater than DFOB alone, and the IC(50) value of this adduct was 6- or 15-fold greater than DFOB in two different cell types. The relationship between logP and (59)Fe mobilization for the DFOB conjugates showed that maximal mobilization of intracellular (59)Fe occurred at a logP value approximately 2.3. This parameter, rather than the affinity for Fe(III), appears to influence the extent of intracellular (59)Fe mobilization. The low toxicity-high Fe mobilization efficacy of selected adamantane-based DFOB conjugates underscores the potential of these compounds to treat iron overload disease in patients with transfusional-dependent disorders such as beta-thalassemia.

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Synthesis of dihydrofuroaporphine derivatives: identification of a potent and selective serotonin 5-HT 1A receptor agonist.

Publication Date: 2010 Feb 11 PMID: 20041669
Authors: Liu, Z. - Zhang, H. - Ye, N. - Zhang, J. - Wu, Q. - Sun, P. - Li, L. - Zhen, X. - Zhang, A.
Journal: J Med Chem

A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT(1A) receptor with K(i) values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [(35)S]GTP gamma S function assays on 5-HT(1A) receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT(1A) receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.

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Optimization of a pipemidic acid autotaxin inhibitor.

Publication Date: 2010 Feb 11 PMID: 20041668
Authors: Hoeglund, A. B. - Bostic, H. E. - Howard, A. L. - Wanjala, I. W. - Best, M. D. - Baker, D. L. - Parrill, A. L.
Journal: J Med Chem

Autotaxin (ATX, NPP2) has recently been shown to be the lysophospholipase D responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA). LPA has a well-established role in cancer, and the production of LPA is consistent with the cancer-promoting actions of ATX. Increased ATX and LPA receptor expression have been found in numerous cancer cell types. The current study has combined ligand-based computational approaches (binary quantitative structure-activity relationship), medicinal chemistry, and experimental enzymatic assays to optimize a previously identified small molecule ATX inhibitor, H2L 7905958 (1). Seventy prospective analogs were analyzed via computational screening, from which 30 promising compounds were synthesized and screened to assess efficacy, potency, and mechanism of inhibition. This approach has identified four analogs as potent as or more potent than the lead. The most potent analog displayed an IC(50) of 900 nM with respect to ATX-mediated FS-3 hydrolysis with a K(i) of 700 nM, making this compound approximately 3-fold more potent than the previously described lead.

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Synthesis and characterization of iodinated tetrahydroquinolines targeting the G protein-coupled estrogen receptor GPR30.

Publication Date: 2010 Feb 11 PMID: 20041667
Authors: Ramesh, C. - Nayak, T. K. - Burai, R. - Dennis, M. K. - Hathaway, H. J. - Sklar, L. A. - Prossnitz, E. R. - Arterburn, J. B.
Journal: J Med Chem

A series of iodo-substituted tetrahydro-3H-cyclopenta[c]quinolines was synthesized as potential targeted imaging agents for the G protein-coupled estrogen receptor GPR30. The affinity and specificity of binding to GPR30 versus the classical estrogen receptors ER alpha/beta and functional responses associated with ligand-binding were determined. Selected iodo-substituted tetrahydro-3H-cyclopenta[c]quinolines exhibited IC(50) values lower than 20 nM in competitive binding studies with GPR30-expressing human endometrial cancer cells. These compounds functioned as antagonists of GPR30 and blocked estrogen-induced PI3K activation and calcium mobilization. The tributylstannyl precursors of selected compounds were radiolabeled with (125)I using the iodogen method. In vivo biodistribution studies in female ovariectomized athymic (NCr) nu/nu mice bearing GPR30-expressing human endometrial tumors revealed GPR30-mediated uptake of the radiotracer ligands in tumor, adrenal, and reproductive organs. Biodistribution and quantitative SPECT/CT studies revealed structurally related differences in the pharmacokinetic profiles, target tissue uptake, and metabolism of the radiolabeled compounds as well as differences in susceptibility to deiodination. The high lipophilicity of the compounds adversely affects the in vivo biodistribution and clearance of these radioligands and suggests that further optimization of this parameter may lead to improved targeting characteristics.

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Catalysis and inhibition of Mycobacterium tuberculosis methionine aminopeptidase.

Publication Date: 2010 Feb 11 PMID: 20038112
Authors: Lu, J. P. - Chai, S. C. - Ye, Q. Z.
Journal: J Med Chem

Methionine aminopeptidase (MetAP) carries out an important cotranslational N-terminal methionine excision of nascent proteins and represents a potential target to develop antibacterial and antitubercular drugs. We cloned one of the two MetAPs in Mycobacterium tuberculosis (MtMetAP1c from the mapB gene) and purified it to homogeneity as an apoenzyme. Its activity required a divalent metal ion, and Co(II), Ni(II), Mn(II), and Fe(II) were among activators of the enzyme. Co(II) and Fe(II) had the tightest binding, while Ni(II) was the most efficient cofactor for the catalysis. MtMetAP1c was also functional in E. coli cells because a plasmid-expressed MtMetAP1c complemented the essential function of MetAP in E. coli and supported the cell growth. A set of potent MtMetAP1c inhibitors were identified, and they showed high selectivity toward the Fe(II)-form, the Mn(II)-form, or the Co(II) and Ni(II) forms of the enzyme, respectively. These metalloform selective inhibitors were used to assign the metalloform of the cellular MtMetAP1c. The fact that only the Fe(II)-form selective inhibitors inhibited the cellular MtMetAP1c activity and inhibited the MtMetAP1c-complemented cell growth suggests that Fe(II) is the native metal used by MtMetAP1c in an E. coli cellular environment. Finally, X-ray structures of MtMetAP1c in complex with three metalloform-selective inhibitors were analyzed, which showed different binding modes and different interactions with metal ions and active site residues.

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Novel synthesis and structural characterization of a high-affinity paramagnetic kinase probe for the identification of non-ATP site binders by nuclear magnetic resonance.

Publication Date: 2010 Feb 11 PMID: 20038108
Authors: Moy, F. J. - Lee, A. - Gavrin, L. K. - Xu, Z. B. - Sievers, A. - Kieras, E. - Stochaj, W. - Mosyak, L. - McKew, J. - Tsao, D. H.
Journal: J Med Chem

To aid in the pursuit of selective kinase inhibitors, we have developed a unique ATP site binder tool for the detection of binders outside the ATP site by nuclear magnetic resonance (NMR). We report here the novel synthesis that led to this paramagnetic spin-labeled pyrazolopyrimidine probe (1), which exhibits nanomolar inhibitory activity against multiple kinases. We demonstrate the application of this probe by performing NMR binding experiments with Lck and Src kinases and utilize it to detect the binding of two compounds proximal to the ATP site. The complex structure of the probe with Lck is also presented, revealing how the probe fits in the ATP site and the specific interactions it has with the protein. We believe that this spin-labeled probe is a valuable tool that holds broad applicability in a screen for non-ATP site binders.

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Development of (S)-N6-(2-(4-(isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tet rahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: potent in vivo activity in Parkinson's disease animal models.

Publication Date: 2010 Feb 11 PMID: 20038106
Authors: Ghosh, B. - Antonio, T. - Zhen, J. - Kharkar, P. - Reith, M. E. - Dutta, A. K.
Journal: J Med Chem

Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (K(i)). Functional activity of selected compounds in stimulating GTPgammaS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (-)-24c (D-301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC(50) (GTP gamma S); D3 = 0.52 nM; D2/D3 (EC(50)): 223). Compounds (-)-24b and (-)-24c exhibited potent radical scavenging activity. The two lead compounds, (-)-24b and (-)-24c, exhibited high in vivo activity in two Parkinson's disease (PD) animal models, reserpinized rat model and 6-OHDA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD.

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Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics.

Publication Date: 2010 Feb 11 PMID: 20038105
Authors: Becker, G. L. - Sielaff, F. - Than, M. E. - Lindberg, I. - Routhier, S. - Day, R. - Lu, Y. - Garten, W. - Steinmetzer, T.
Journal: J Med Chem

Furin belongs to the family of proprotein convertases (PCs) and is involved in numerous normal physiological and pathogenic processes, such as viral propagation, bacterial toxin activation, cancer, and metastasis. Furin and related furin-like PCs cleave their substrates at characteristic multibasic consensus sequences, preferentially after an arginine residue. By incorporating decarboxylated arginine mimetics in the P1 position of substrate analogue peptidic inhibitors, we could identify highly potent furin inhibitors. The most potent compound, phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide (15), inhibits furin with a K(i) value of 0.81 nM and has also comparable affinity to other PCs like PC1/3, PACE4, and PC5/6, whereas PC2 and PC7 or trypsin-like serine proteases were poorly affected. In fowl plague virus (influenza A, H7N1)-infected MDCK cells, inhibitor 15 inhibited proteolytic hemagglutinin cleavage and was able to reduce virus propagation in a long-term infection test. Molecular modeling revealed several key interactions of the 4-amidinobenzylamide residue in the S1 pocket of furin contributing to the excellent affinity of these inhibitors.

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Benzo[e]isoindole-1,3-diones as potential inhibitors of glycogen synthase kinase-3 (GSK-3). Synthesis, kinase inhibitory activity, zebrafish phenotype, and modeling of binding mode.

Publication Date: 2010 Feb 11 PMID: 20030405
Authors: Zou, H. - Zhou, L. - Li, Y. - Cui, Y. - Zhong, H. - Pan, Z. - Yang, Z. - Quan, J.
Journal: J Med Chem

Benzo[e]isoindole-1,3-dione derivatives were synthesized, and the effects on GSK-3beta activity and zebrafish embryo growth were evaluated. A series of derivatives show obvious inhibitory activity against GSK-3beta. The most potent inhibitor, 7,8-dimethoxy-5-methylbenzo[e]isoindole-1,3-dione (8a), shows nanomolar IC(50) and obvious phenotype on zebrafish embryo growth associated with the inhibition of GSK-3beta at low micromolar concentration. The interaction mode between 8a and GSK-3beta was characterized by computational modeling.

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Novel 3-arylideneindolin-2-ones as inhibitors of NAD+ -dependent histone deacetylases (sirtuins).

Publication Date: 2010 Feb 11 PMID: 20030343
Authors: Huber, K. - Schemies, J. - Uciechowska, U. - Wagner, J. M. - Rumpf, T. - Lewrick, F. - Suss, R. - Sippl, W. - Jung, M. - Bracher, F.
Journal: J Med Chem

Class III histone deacetylases (sirtuins) play pivotal roles in many cellular processes. They are linked to extended lifespan and to the pathogenesis of cancer and neuronal disorders. We present novel sirtuin inhibitors based on a 6,7-dichloro-2-oxindole scaffold with low micromolar activity. In vitro activity was rationalized by docking studies, and hyperacetylation of sirtuin targets could be demonstrated in cell culture.

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Evaluation of substituted N,N'-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase.

Publication Date: 2010 Feb 11 PMID: 20017496
Authors: Boxer, M. B. - Jiang, J. K. - Vander Heiden, M. G. - Shen, M. - Skoumbourdis, A. P. - Southall, N. - Veith, H. - Leister, W. - Austin, C. P. - Park, H. W. - Inglese, J. - Cantley, L. C. - Auld, D. S. - Thomas, C. J.
Journal: J Med Chem

The metabolism of cancer cells is altered to support rapid proliferation. Pharmacological activators of a tumor cell specific pyruvate kinase isozyme (PKM2) may be an approach for altering the classic Warburg effect characteristic of aberrant metabolism in cancer cells yielding a novel antiproliferation strategy. In this manuscript, we detail the discovery of a series of substituted N,N'-diarylsulfonamides as activators of PKM2. The synthesis of numerous analogues and the evaluation of structure-activity relationships are presented as well as assessments of mechanism and selectivity. Several agents are found that have good potencies and appropriate solubility for use as chemical probes of PKM2 including 55 (AC(50) = 43 nM, maximum response = 84%; solubility = 7.3 microg/mL), 56 (AC(50) = 99 nM, maximum response = 84%; solubility = 5.7 microg/mL), and 58 (AC(50) = 38 nM, maximum response = 82%; solubility = 51.2 microg/mL). The small molecules described here represent first-in-class activators of PKM2.

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Design and synthesis of 5,5'-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors.

Publication Date: 2010 Feb 11 PMID: 19968289
Authors: Malamas, M. S. - Erdei, J. - Gunawan, I. - Turner, J. - Hu, Y. - Wagner, E. - Fan, K. - Chopra, R. - Olland, A. - Bard, J. - Jacobsen, S. - Magolda, R. L. - Pangalos, M. - Robichaud, A. J.
Journal: J Med Chem

The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001).

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Perspectives of p-glycoprotein modulating agents in oncology and neurodegenerative diseases: pharmaceutical, biological, and diagnostic potentials.

Publication Date: 2010 Mar 11 PMID: 19924994
Authors: Colabufo, N. A. - Berardi, F. - Cantore, M. - Contino, M. - Inglese, C. - Niso, M. - Perrone, R.
Journal: J Med Chem

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Structure-activity relationships of polymyxin antibiotics.

Publication Date: 2010 Mar 11 PMID: 19874036
Authors: Velkov, T. - Thompson, P. E. - Nation, R. L. - Li, J.
Journal: J Med Chem

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Highlights in the discovery of antiviral drugs: a personal retrospective.

Publication Date: 2010 Feb 25 PMID: 19860424
Authors: De Clercq, E.
Journal: J Med Chem

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18F stilbenes and styrylpyridines for PET imaging of A beta plaques in Alzheimer's disease: a miniperspective.

Publication Date: 2010 Feb 11 PMID: 19845387
Authors: Kung, H. F. - Choi, S. R. - Qu, W. - Zhang, W. - Skovronsky, D.
Journal: J Med Chem

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Scope and difficulty in generating theoretical insights regarding ligand recognition and activation of the beta 2 adrenergic receptor.

Publication Date: 2010 Feb 11 PMID: 19803522
Authors: Soriano-Ursua, M. A. - Trujillo-Ferrara, J. G. - Correa-Basurto, J.
Journal: J Med Chem

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