J. Med. Chem.

Development and Experimental Validation of a Docking Strategy for the Generation of Kinase-Targeted Libraries.

Publication Date: 2008 May 15 PMID: 18479119
Authors: Gozalbes, R. - Simon, L. - Froloff, N. - Sartori, E. - Monteils, C. - Baudelle, R.
Journal: J Med Chem

A high-throughput docking strategy for the filtering of in silico compounds and the generation of kinase-targeted libraries is described. Systematic docking and scoring in three kinase crystal 3D structures of 123 structurally diverse kinase ligands led to the determination of six thresholds for each kinase. These thresholds were used as filters for the virtual screening of two collections of compounds: a collection of more than 2500 drugs and drug-like compounds (negative control) and a kinase-targeted library of 1440 compounds. This strategy was then experimentally validated by testing 60 compounds from the kinase-targeted library on 41 kinases from five different families. The 60 compounds were split into those passing all the thresholds and the others (30 compounds in each group). The overall hit enrichment was 6.70-fold higher in the first group, validating our approach for the generation of kinase-targeted libraries and the identification of scaffolds with high kinase inhibitory potential.

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Exploiting Protein Fluctuations at the Active-Site Gorge of Human Cholinesterases: Further Optimization of the Design Strategy to Develop Extremely Potent Inhibitors.

Publication Date: 2008 May 15 PMID: 18479118
Authors: Butini, S. - Campiani, G. - Borriello, M. - Gemma, S. - Panico, A. - Persico, M. - Catalanotti, B. - Ros, S. - Brindisi, M. - Agnusdei, M. - Fiorini, I. - Nacci, V. - Novellino, E. - Belinskaya, T. - Saxena, A. - Fattorusso, C.
Journal: J Med Chem

Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase ( hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.

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Histone Deacetylase Inhibitors: From Bench to Clinic.

Publication Date: 2008 May 15 PMID: 18479117
Authors: Paris, M. - Porcelloni, M. - Binaschi, M. - Fattori, D.
Journal: J Med Chem

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Synthesis and Evaluation of [2-(4-Quinolyloxy)phenyl]methanone Derivatives: Novel Selective Inhibitors of Transforming Growth Factor-beta Kinase.

Publication Date: 2008 May 15 PMID: 18479116
Authors: Shimizu, T. - Kimura, K. - Sakai, T. - Kawakami, K. - Miyazaki, T. - Nakouji, M. - Ogawa, A. - Ohuchi, H. - Shimizu, K.
Journal: J Med Chem

We synthesized and evaluated various [2-(4-quinolyloxy)phenyl]methanone derivatives. These compounds had novel chemical structures that were distinct from those of previously reported inhibitors. Biological data suggested that these compounds inhibited transforming growth factor-beta signaling by interacting with the ATP-binding pocket of the transforming growth factor-beta type I receptor kinase domain. Here, we report on the synthesis and structure-activity relationships of the compounds in this series.

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Synthesis and in Vitro Antiprotozoal Activities of Water-Soluble, Inexpensive 3,7-Bis(dialkylamino)phenoxazin-5-ium Derivatives.

Publication Date: 2008 May 14 PMID: 18476684
Authors: Ge, J. F. - Arai, C. - Kaiser, M. - Wittlin, S. - Brun, R. - Ihara, M.
Journal: J Med Chem

3,7-Bis(dialkylamino)phenoxazinium salts were synthesized and evaluated for in vitro activities against Plasmodium falciparum, Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania donovani. Notably, the compounds showed potent antiprotozoal activities, especially against P. falciparum and T. cruzi. The compounds with alkyl side chains less than three carbons in length possessed good activities with high selective indices.

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Antitumor Agents 260. New Desmosdumotin B Analogues with Improved In Vitro Anticancer Activity.

Publication Date: 2008 May 13 PMID: 18473435
Authors: Nakagawa-Goto, K. - Bastow, K. F. - Chen, T. H. - Morris-Natschke, S. L. - Lee, K. H.
Journal: J Med Chem

Sixteen analogues ( 3-16, 33, and 48) of the unique flavonoid desmosdumotin B ( 1) were prepared and evaluated as in vitro inhibitors of the human KB cancer cell line and its MDR subclone, KB-VIN. 6,8,8-Triethyl analogues 10- 13 showed enhanced KB-VIN selectivity. In particular, 4'-alkyl derivatives 11 (4'-Me) and 12 (4'-Et) showed significant ED 50 values of 0.03 and 0.025 microg/mL, respectively, against KB-VIN with selectivities of >460- and 320-fold compared with that of KB. This report is the first to describe compounds showing such high activity against MDR cells versus non-MDR cells. The unique activity of 1-analogues is likely MDR-mediated because cotreatment with verapamil, a P-gp inhibitor, partially reversed the selective toxicity of both 1 and 10. Interestingly, only 1-analogues with a naphthalene B-ring ( 8 and 14) showed significant cytotoxic activity against KB and other cancer cell lines. Thus, 1-analogues might be a new class of potent drug candidates, especially as 11 and 12 express direct selective action against tumors expressing MDR.

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Novel Inhibitors of the v-raf Murine Sarcoma Viral Oncogene Homologue B1 (BRAF) Based on a 2,6-Disubstituted Pyrazine Scaffold.

Publication Date: 2008 May 13 PMID: 18473434
Authors: Niculescu-Duvaz, I. - Roman, E. - Whittaker, S. R. - Friedlos, F. - Kirk, R. - Scanlon, I. J. - Davies, L. C. - Niculescu-Duvaz, D. - Marais, R. - Springer, C. J.
Journal: J Med Chem

BRAF, a serine/threonine kinase, plays a key role in the development of certain types of cancer, particularly melanoma. 2-(3,4,5-Trimethoxyphenylamino)-6-(3-acetamidophenyl)-pyrazine, 1, was identified as a low micromolar (IC 50 = 3.5 microM) BRAF inhibitor from a high-throughput screen of a library of 23000 compounds. This compound was chosen as the starting point of a program aimed at developing inhibitors of mutant (V600E)BRAF. We have already reported on the optimization of the trimethoxyphenylamino moiety of 1. In this paper, we describe the synthesis of a series of compounds derived from 1 with the purpose of optimization of the pyrazine central core and the phenylacetamido moiety in order to increase the potency against (V600E)BRAF compared to CRAF. The biological activity of the new inhibitors was assessed against mutant (V600E)BRAF in vitro. Several compounds were identified with IC 50s of 300-500 nM for (V600E)BRAF, and all compounds that were assessed showed selectivity for (V600E)BRAF compared to CRAF by 5->86-fold.

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Development of Novel Antiatherogenic Biaryls: Design, Synthesis, and Reactivity.

Publication Date: 2008 May 9 PMID: 18465848
Authors: Delomenede, M. - Bedos-Belval, F. - Duran, H. - Vindis, C. - Baltas, M. - Negre-Salvayre, A.
Journal: J Med Chem

On the basis of the 5,5'-bisvanillin scaffold, a series of compounds has been synthesized presenting symmetric or dissymmetric frames on each phenolic moiety. These frames are alpha,beta-unsaturated (fluoro)phosphonate and/or alpha,beta-unsaturated hydrazone(s) formed by coupling aldehydic with isoniazid or hydralazine. All compounds were tested for their ability to inhibit cell-mediated low-density lipoprotein oxidation. Oxidized low-density lipoprotein induced cytotoxicity was also evaluated along with the carbonyl scavenger properties of selected compounds. The most efficient agents were found to be those possessing at least one hydralazinone frame, with the most potent being the symmetrical compound: 4,4'-dihydroxy-3,3'-dimethoxy-5,5'-biphenyl-1,1'-(diphthalazin-1-yl)methyl hydrazone hydrochloride.

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Novel Substituted Aminoalkylguanidines as Potential Antihyperglycemic and Food Intake-Reducing Agents.

Publication Date: 2008 May 9 PMID: 18465847
Authors: Tassoni, E. - Giannessi, F. - Brunetti, T. - Pessotto, P. - Renzulli, M. - Travagli, M. - Rajamaki, S. - Prati, S. - Dottori, S. - Corelli, F. - Cabri, W. - Carminati, P. - Botta, M.
Journal: J Med Chem

We report the synthesis and evaluation of aminoalkylguanidine analogues and derivatives in C57BL/KsJ db/db diabetic mice, following identification by random screening of 1a and 1b as potential antihyperglycemics and/or modulators of food intake. These compounds are related to galegine, a gamma,gamma-dimethylallylguanidine. Between the newly identified compounds, 1h N-(cyclopropylmethyl)- N'-(4-(aminomethyl)cyclohexylmethyl)guanidine showed the most balanced activity as antihyperglycemic and food intake-reducing agent.

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Design, Synthesis, and Biological Evaluation of New-Generation Taxoids.

Publication Date: 2008 May 9 PMID: 18465846
Authors: Ojima, I. - Chen, J. - Sun, L. - Borella, C. P. - Wang, T. - Miller, M. L. - Lin, S. - Geng, X. - Kuznetsova, L. - Qu, C. - Gallager, D. - Zhao, X. - Zanardi, I. - Xia, S. - Horwitz, S. B. - Mallen-St Clair, J. - Guerriero, J. L. - Bar-Sagi, D. - Veith, J. M. - Pera, P. - Bernacki, R. J.
Journal: J Med Chem

Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in beta-tubulin as well, wherein the drug resistance is mediated by the beta-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.

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Modulating the Therapeutic Activity of Nanoparticle Delivered Paclitaxel by Manipulating the Hydrophobicity of Prodrug Conjugates.

Publication Date: 2008 May 9 PMID: 18465845
Authors: Ansell, S. M. - Johnstone, S. A. - Tardi, P. G. - Lo, L. - Xie, S. - Shu, Y. - Harasym, T. O. - Harasym, N. L. - Williams, L. - Bermudes, D. - Liboiron, B. D. - Saad, W. - Prud'homme, R. K. - Mayer, L. D.
Journal: J Med Chem

A series of paclitaxel prodrugs designed for formulation in lipophilic nanoparticles are described. The hydrophobicity of paclitaxel was increased by conjugating a succession of increasingly hydrophobic lipid anchors to the drug using succinate or diglycolate cross-linkers. The prodrugs were formulated in well defined block copolymer-stabilized nanoparticles. These nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo. The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release half-lives ranging from 1 to 24 h. The diglycolate and succinate cross-linked prodrugs were 1-2 orders of magnitude less potent than paclitaxel in vitro. Nanoparticle formulations of the succinate prodrugs showed no evidence of efficacy in HT29 human colorectal tumor xenograph models. Efficacy of diglycolate prodrug nanoparticles increased as the anchor hydrophobicity increased. Long circulating diglycolate prodrug nanoparticles provided significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose.

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Design and Synthesis of FAJANU: a de Novo C2 Symmetric Cyclopeptide Family.

Publication Date: 2008 May 8 PMID: 18461923
Authors: Garcia-Martin, F. - Cruz, L. J. - Rodriguez-Mias, R. A. - Giralt, E. - Albericio, F.
Journal: J Med Chem

A novel cyclic peptide has been designed from several potent marine cytotoxic peptides, including IB-01212, luzopeptin, triostin, and thiocoraline. The FAJANU scaffold maintains C 2 symmetry, cyclic structure, and the construction of aromatic and aliphatic character at the N- and C-terminal extremes. A first six-member family was previously synthesized and evaluated biologically. Several analogues presented greater activity than IB-01212. Furthermore, on the basis of the most active candidate, we have performed a more exhaustive synthetic and structural analysis: (i) structure-activity relationship provided clues about the key elements in the framework, (ii) NMR assignment confirmed C 2 symmetry, and (iii) confocal images revealed its penetration and cellular localization.

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A Prodomain Peptide of Plasmodium falciparum Cysteine Protease (Falcipain-2) Inhibits Malaria Parasite Development.

Publication Date: 2008 May 8 PMID: 18461922
Authors: Korde, R. - Bhardwaj, A. - Singh, R. - Srivastava, A. - Chauhan, V. S. - Bhatnagar, R. K. - Malhotra, P.
Journal: J Med Chem

Falcipain-2 (FP-2), a papain family cysteine protease of Plasmodium falciparum, is a promising target for antimalarial chemotherapy. Designing inhibitors that are highly selective for falcipain-2 has been difficult because of broad specificity of different cysteine proteinases. Because propeptide regions of cysteine proteases have been shown to inhibit their cognate enzymes specifically and selectively, in the present study, we evaluated the inhibitory potential of few falcipain-2 proregion peptides. A 15 residue peptide (PP1) inhibited falcipain-2 enzyme activity in vitro. Studies on the uptake of PP1 into the parasitized erythrocytes showed access of peptide into the infected RBCs. PP1 fused with Antennapedia homeoprotein internalization domain blocked hemoglobin hydrolysis, merozoite release and markedly inhibited Plasmodium falciparum growth and maturation. Together, our results identify a peptide derived from the proregion of falcipain-2 that blocks late-stage malaria parasite development in RBCs, suggesting the development of peptide and peptidometric drugs against the human malaria parasite.

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Trifluoromethoxyl Substituted Phenylethylene Diamines as High Affinity sigma Receptor Ligands with Potent Anti-Cocaine Actions.

Publication Date: 2008 May 8 PMID: 18461921
Authors: Smith, T. A. - Yang, X. - Wu, H. - Pouw, B. - Matsumoto, R. R. - Coop, A.
Journal: J Med Chem

The phenylethylene diamines are a class of sigma receptor ligands with excellent selectivity over other biological systems and with anti-cocaine actions that involve antagonism of sigma 1 receptors. In order to increase the potency of the aromatic methoxyl substituted analogues, trifluoromethoxyl groups were introduced to prevent metabolic demethylation. The para-substituted trifluoromethoxyl substituted analogues were shown to have increased sigma receptor affinity and represent the most potent anti-cocaine phenylethylene diamines yet described.

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Discovery of Novel Human Histamine H4 Receptor Ligands by Large-Scale Structure-Based Virtual Screening.

Publication Date: 2008 May 7 PMID: 18459760
Authors: Kiss, R. - Kiss, B. - Konczol, A. - Szalai, F. - Jelinek, I. - Laszlo, V. - Noszal, B. - Falus, A. - Keseru, G. M.
Journal: J Med Chem

A structure-based virtual screening (SBVS) was conducted on a ligand-supported homology model of the human histamine H4 receptor (hH4R). More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the hH4R binding site using FlexX. A total of 255 selected compounds were tested by radioligand binding assay and 16 of them possessed significant [ (3)H]histamine displacement. Several novel scaffolds were identified that can be used to develop selective H4 ligands in the future. As far as we know, this is the first SBVS reported on H4R, representing one of the largest virtual screens validated by the biological evaluation of the virtual hits.

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Microsomal Prostaglandin E2 Synthase-1 (mPGES-1): A Novel Anti-Inflammatory Therapeutic Target.

Publication Date: 2008 May 7 PMID: 18459759
Authors: Friesen, R. W. - Mancini, J. A.
Journal: J Med Chem

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Guanidine and 2-Aminoimidazoline Aromatic Derivatives as alpha2-Adrenoceptor Antagonists. 2. Exploring Alkyl Linkers for New Antidepressants.

Publication Date: 2008 May 7 PMID: 18459731
Authors: Rodriguez, F. - Rozas, I. - Ortega, J. E. - Erdozain, A. M. - Meana, J. J. - Callado, L. F.
Journal: J Med Chem

The preparation of a number of (bis)guanidine and (bis)2-aminoimidazoline derivatives as potential alpha 2-adrenoceptor antagonists for the treatment of depression is presented. Human brain tissue was used to measure their affinity toward the alpha 2-adrenoceptors in vitro. Compounds 6b, 8b, 9b, 10b, 15b, 17b, 18b, 20b, and 21b displayed a good affinity (p K i > 7) and were evaluated in in vitro functional [ (35)S]GTPgammaS binding assays in human prefrontal cortex to determine their agonistic or antagonistic activity. Among these compounds, 17b and 20b showed the expected behavior for an antagonist and were subject to in vivo microdialysis experiments in rats. Significantly, these experiments confirmed the antagonistic properties of 17b and 20b, and therefore both compounds can be considered as potential antidepressants.

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Novel 3-Carboxamide-coumarins as Potent and Selective FXIIa Inhibitors.

Publication Date: 2008 May 7 PMID: 18459730
Authors: Robert, S. - Bertolla, C. - Masereel, B. - Dogne, J. M. - Pochet, L.
Journal: J Med Chem

Recently, FXIIa was highlighted as an original attractive target for the development of new anticoagulant drugs with low rates of therapy-related hemorrhages. In this work, we describe the development of a new series of 3-carboxamide-coumarins that are the first potent and selective nonpeptidic inhibitors of FXIIa.

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Prediction and Identification of Drug Interactions with the Human ATP-Binding Cassette Transporter Multidrug-Resistance Associated Protein 2 (MRP2; ABCC2).

Publication Date: 2008 May 6 PMID: 18457386
Authors: Pedersen, J. M. - Matsson, P. - Bergstrom, C. A. - Norinder, U. - Hoogstraate, J. - Artursson, P.
Journal: J Med Chem

The chemical space of registered oral drugs was explored for inhibitors of the human multidrug-resistance associated protein 2 (MRP2; ABCC2), using a data set of 191 structurally diverse drugs and drug-like compounds. The data set included a new reference set of 75 compounds, for studies of hepatic drug interactions with transport proteins, CYP enzymes, and compounds associated with liver toxicity. The inhibition of MRP2-mediated transport of estradiol-17beta- d-glucuronide was studied in inverted membrane vesicles from Sf9 cells overexpressing human MRP2. A total of 27 previously unknown MRP2 inhibitors were identified, and the results indicate an overlapping but narrower inhibitor space for MRP2 compared with the two other major ABC efflux transporters P-gp (ABCB1) and BCRP (ABCG2). In addition, 13 compounds were shown to stimulate the transport of estradiol-17beta- d-glucuronide. The experimental results were used to develop a computational model able to discriminate inhibitors from noninhibitors according to their molecular structure, resulting in a predictive power of 86% for the training set and 72% for the test set. The inhibitors were in general larger and more lipophilic and presented a higher aromaticity than the noninhibitors. The developed computational model is applicable in an early stage of the drug discovery process and is proposed as a tool for prediction of MRP2-mediated hepatic drug interactions and toxicity.

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Recent Developments in Fragment-Based Drug Discovery.

Publication Date: 2008 May 6 PMID: 18457385
Authors: Congreve, M. - Chessari, G. - Tisi, D. - Woodhead, A. J.
Journal: J Med Chem

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Lavendamycin Antitumor Agents: Structure-Based Design, Synthesis, and NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Model Validation with Molecular Docking and Biological Studies.

Publication Date: 2008 May 6 PMID: 18457384
Authors: Hassani, M. - Cai, W. - Koelsch, K. H. - Holley, D. C. - Rose, A. S. - Olang, F. - Lineswala, J. P. - Holloway, W. G. - Gerdes, J. M. - Behforouz, M. - Beall, H. D.
Journal: J Med Chem

A 1H69 crystal structure-based in silico model of the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site has been developed to facilitate NQO1-directed lavendamycin antitumor agent development. Lavendamycin analogues were designed as NQO1 substrates utilizing structure-based design criteria. Computational docking studies were performed using the model to predict NQO1 substrate specificity. Designed N-acyllavendamycin esters and amides were synthesized by Pictet-Spengler condensation. Metabolism and cytotoxicity studies were performed on the analogues with recombinant human NQO1 and human colon adenocarcinoma cells (NQO1-deficient BE and NQO1-rich BE-NQ). Docking and biological data were found to be correlated where analogues 12, 13, 14, 15, and 16 were categorized as good, poor, poor, poor, and good NQO1 substrates, respectively. Our results demonstrated that the ligand design criteria were valid, resulting in the discovery of two good NQO1 substrates. The observed consistency between the docking and biological data suggests that the model possesses practical predictive power.

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Synthesis and Antibacterial Activity of Novel Pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic Acid Derivatives Carrying the 3-Cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl Group as a C-10 Substituent.

Publication Date: 2008 May 6 PMID: 18457383
Authors: Asahina, Y. - Takei, M. - Kimura, T. - Fukuda, Y.
Journal: J Med Chem

Novel pyrido[1,2,3- de][1,4]benzoxazine-6-carboxylic acid derivatives 5- 9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.

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Benzoylurea Derivatives as a Novel Class of Antimitotic Agents: Synthesis, Anticancer Activity, and Structure-Activity Relationships.

Publication Date: 2008 May 6 PMID: 18457382
Authors: Song, D. Q. - Wang, Y. - Wu, L. Z. - Yang, P. - Wang, Y. M. - Gao, L. M. - Li, Y. - Qu, J. R. - Wang, Y. H. - Li, Y. H. - Du, N. N. - Han, Y. X. - Zhang, Z. P. - Jiang, J. D.
Journal: J Med Chem

Forty-six new compounds were synthesized on the basis of our knowledge of the 3-haloacylamino benzoylurea (HBU) series. Structure-activity relationship (SAR) analysis indicates that (i) the configuration of the chiral center in 1 (JIMB01) is not indispensable for the activity, (ii) the phenyl ring is essential, and (iii) a substitution at the 6-position of the phenyl ring with a halogen enhances the activity. Among the analogues, 11e and 14b bearing 6-fluoro substitution showed potent activities against nine human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), PC-3 (prostate cancer), DND-1A(melanoma), LOVO (colon cancer), and MIA Paca (pancreatic cancer) with IC 50 values between 0.01 and 0.30 microM. 14b inhibited human hepatocarcinoma by 86% in volume in nude mice. The mechanism of 14b is to inhibit microtubule assembly, followed by the M-phase arrest, bcl-2 inactivation, and then apoptosis. We consider 14b promising for further anticancer investigation.

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Second Generation of Hydroxyethylamine BACE-1 Inhibitors: Optimizing Potency and Oral Bioavailability.

Publication Date: 2008 May 6 PMID: 18457381
Authors: Charrier, N. - Clarke, B. - Cutler, L. - Demont, E. - Dingwall, C. - Dunsdon, R. - East, P. - Hawkins, J. - Howes, C. - Hussain, I. - Jeffrey, P. - Maile, G. - Matico, R. - Mosley, J. - Naylor, A. - O'Brien, A. - Redshaw, S. - Rowland, P. - Soleil, V. - Smith, K. J. - Sweitzer, S. - Theobald, P. - Vesey, D. - Walter, D. S. - Wayne, G.
Journal: J Med Chem

BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.

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Tuning the DNA Conformational Perturbations Induced by Cytotoxic Platinum-Acridine Bisintercalators: Effect of Metal Cis/Trans Isomerism and DNA Threading Groups.

Publication Date: 2008 May 6 PMID: 18457380
Authors: Choudhury, J. R. - Guddneppanavar, R. - Saluta, G. - Kucera, G. L. - Bierbach, U.
Journal: J Med Chem

Four highly charged, water soluble platinum-acridine bisintercalating agents have been synthesized. Depending on the cis/trans isomerism of the metal and the nature of the acridine side chains, bisintercalation induces/stabilizes the classical Watson-Crick B-form or a non-B-form. Circular dichroism spectra and chemical footprinting experiments suggest that 4, the most active derivative in HL-60 cells, produces a structurally severely perturbed DNA with features of a Hoogsteen base-paired biopolymer.

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Acetic Acid Aldose Reductase Inhibitors Bearing a Five-Membered Heterocyclic Core with Potent Topical Activity in a Visual Impairment Rat Model.

Publication Date: 2008 May 2 PMID: 18452283
Authors: La Motta, C. - Sartini, S. - Salerno, S. - Simorini, F. - Taliani, S. - Marini, A. M. - Da Settimo, F. - Marinelli, L. - Limongelli, V. - Novellino, E.
Journal: J Med Chem

A number of 1,2,4-oxadiazol-5-yl-acetic acids and oxazol-4-yl-acetic acids were synthesized and tested for their ability to inhibit aldose reductase (ALR2). The oxadiazole derivatives, 7c, 7f, 7i, and 8h, 8i, proved to be the most active compounds, exhibiting inhibitory levels in the submicromolar range. In this series, the phenyl group turned out to be the preferred substitution pattern, as its lengthening to a benzyl moiety determined a general reduction of the inhibitory potency. The lead compound, 2-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]acetic acid, 7c, showed an excellent in vivo activity, proving to prevent cataract development in severely galactosemic rats when administered as an eye-drop solution in the precorneal region of the animals. Computational studies on the ALR2 inhibitors were performed to rationalize the structure-activity relationships observed and to provide the basis for further structure-guided design of novel ALR2 inhibitors.

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Activity-Based Probe for Specific Photoaffinity Labeling gamma-Aminobutyric Acid B (GABAB) Receptors on Living Cells: Design, Synthesis, and Biological Evaluation.

Publication Date: 2008 May 1 PMID: 18447381
Authors: Li, X. - Cao, J. H. - Li, Y. - Rondard, P. - Zhang, Y. - Yi, P. - Liu, J. F. - Nan, F. J.
Journal: J Med Chem

A trimodular activity-based probe was designed, synthesized, characterized, and applied to photoaffinity label the GABA B receptors transiently expressed in Chinese hamster ovary (CHO) cells. The probe exhibits specific binding activity at the ligand-binding pocket of GB1 subunits and high specificity of photoaffinity labeling, which makes the probe valuable for studying the localization and function of GABA B receptors on living cells.

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Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity.

Publication Date: 2008 May 1 PMID: 18447380
Authors: Chackalamannil, S. - Wang, Y. - Greenlee, W. J. - Hu, Z. - Xia, Y. - Ahn, H. S. - Boykow, G. - Hsieh, Y. - Palamanda, J. - Agans-Fantuzzi, J. - Kurowski, S. - Graziano, M. - Chintala, M.
Journal: J Med Chem

The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.

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Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit.

Publication Date: 2008 May 1 PMID: 18447379
Authors: Hu, E. - Tasker, A. - White, R. D. - Kunz, R. K. - Human, J. - Chen, N. - Burli, R. - Hungate, R. - Novak, P. - Itano, A. - Zhang, X. - Yu, V. - Nguyen, Y. - Tudor, Y. - Plant, M. - Flynn, S. - Xu, Y. - Meagher, K. L. - Whittington, D. A. - Ng, G. Y.
Journal: J Med Chem

Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.

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Assessment of Scaffold Hopping Efficiency by Use of Molecular Interaction Fingerprints.

Publication Date: 2008 May 1 PMID: 18447336
Authors: Venhorst, J. - Nunez, S. - Terpstra, J. W. - Kruse, C. G.
Journal: J Med Chem

A novel scoring algorithm based on molecular interaction fingerprints (IFPs) was comparatively evaluated in its scaffold hopping efficiency against four virtual screening standards (GlideXP, Gold, ROCS, and a Bayesian classifier). Decoy databases for the two targets under examination, adenosine deaminase and retinoid X receptor alpha, were obtained from the Directory of Useful Decoys and were further enriched with approximately 5% of active ligands. Structure and ligand-based methods were used to generate the ligand poses, and a Tanimoto metric was chosen for the calculation of the similarity interaction fingerprint between the reference ligand and the screening database. Database enrichments were found to strongly depend on the pose generator algorithm. In spite of these dependencies, enrichments using molecular IFPs were comparable to those obtained with GlideXP, Gold, ROCS, and the Bayesian classifier. More interestingly, the molecular IFP scoring algorithm outperformed these methods at scaffold hopping enrichment, regardless of the pose generator algorithm.

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Nitrite Anion: The Key Intermediate in Alkyl Nitrates Degradative Mechanism.

Publication Date: 2008 Apr 29 PMID: 18442229
Authors: Grossi, L.
Journal: J Med Chem

Alkyl nitrates are metabolized in vitro to yield nitric oxide, and thiol groups have long been considered necessary cofactors. Here, we report evidence that no reaction between thiols and alkyl nitrates takes place in vitro, but stronger reducing agents, such as iron(II) derivatives, are necessary; alkoxy radicals and nitrite anions are the reaction intermediates. The latter, in slightly acidic conditions, can nitrosate thiols to the corresponding S-nitrosothiols, the real NO releasers.

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On the Applicability of GPCR Homology Models to Computer-Aided Drug Discovery: A Comparison between In Silico and Crystal Structures of the beta2-Adrenergic Receptor.

Publication Date: 2008 May 22 PMID: 18442228
Authors: Costanzi, S.
Journal: J Med Chem

The publication of the crystal structure of the beta 2-adrenergic receptor (beta 2-AR) proved that G protein-coupled receptors (GPCRs) share a structurally conserved rhodopsin-like 7TM core. Here, to probe to which extent realistic GPCR structures can be recreated through modeling, carazolol was docked at two rhodopsin-based homology models of the human beta 2-AR. The first featured a rhodopsin-like second extracellular loop, which interfered with ligand docking and with the orientation of several residues in the binding pocket. The second featured a second extracellular loop built completely de novo, which afforded a more accurate model of the binding pocket and a better docking of the ligand. Furthermore, incorporating available biochemical and computational data to the model by correcting the conformation of a single residue lining the binding pocket -Phe290(6.52)-, resulted in significantly improved docking poses. These results support the applicability of GPCR modeling to the design of site-directed mutagenesis experiments and to drug discovery.

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Aminoacyl-tRNA Synthetase Inhibitors as Potent and Synergistic Immunosuppressants.

Publication Date: 2008 May 22 PMID: 18438987
Authors: Van de Vijver, P. - Ostrowski, T. - Sproat, B. - Goebels, J. - Rutgeerts, O. - Van Aerschot, A. - Waer, M. - Herdewijn, P.
Journal: J Med Chem

The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5'- O-( N- l-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found these compounds to have potent immunosuppressive activity. Also, we found that combinations of these compounds inhibited the immune response synergistically. Based on these data, analogues with modifications at the aminoacyl and ribose moieties were designed and evaluated, and several of these showed high immunosuppressive potency, with one compound having an IC 50 of 80 nM, when tested in a cellular mixed lymphocyte reaction assay. Apart from showing the potential of aminoacyl-tRNA synthetase inhibitors as immunosuppressants, the current study also provides arguments for careful evaluation of the immunosuppressive activity of developmental antibacterials that target these enzymes.

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Structure-Activity Relationship Studies on N'-Aryl Carbohydrazide P2X7 Antagonists.

Publication Date: 2008 May 22 PMID: 18438986
Authors: Nelson, D. W. - Sarris, K. - Kalvin, D. M. - Namovic, M. T. - Grayson, G. - Donnelly-Roberts, D. L. - Harris, R. - Honore, P. - Jarvis, M. F. - Faltynek, C. R. - Carroll, W. A.
Journal: J Med Chem

N'-Aryl acyl hydrazides were identified as P2X 7 receptor antagonists. Structure-activity relationship (SAR) studies evaluated functional activity by monitoring calcium flux inhibition in cell lines expressing recombinant human and rat P2X 7 receptors. Selected analogs were assayed in vitro for their capacity to inhibit release of cytokine IL-1beta. Compounds with potent antagonist function were evaluated in vivo using the zymosan-induced peritonitis model. A representative compound effectively attenuated mechanical allodynia in a rat model of neuropathic pain.

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4-Benzyl-1H-imidazoles with Oxazoline Termini as Histamine H3 Receptor Agonists.

Publication Date: 2008 May 22 PMID: 18433114
Authors: Wijtmans, M. - Celanire, S. - Snip, E. - Gillard, M. R. - Gelens, E. - Collart, P. P. - Venhuis, B. J. - Christophe, B. - Hulscher, S. - Goot, H. V. - Lebon, F. - Timmerman, H. - Bakker, R. A. - Lallemand, B. I. - Leurs, R. - Talaga, P. E. - Esch, I. J.
Journal: J Med Chem

Research on the therapeutic applications of the histamine H 3 receptor (H 3R) has traditionally focused on antagonists/inverse agonists. In contrast, H 3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H 3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H 3R activation. In the light of these important issues, we present our findings on 4-benzyl-1 H-imidazole-based H 3R agonists. Starting from two high throughput screen hits ( 10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12- 31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H 3R research.

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Discovery of Potent, Orally Bioavailable, Selective 5-HT1A/B/D Receptor Antagonists.

Publication Date: 2008 May 22 PMID: 18433113
Authors: Ward, S. E. - Eddershaw, P. J. - Scott, C. M. - Gordon, L. J. - Lovell, P. J. - Moore, S. H. - Smith, P. W. - Starr, K. R. - Thewlis, K. M. - Watson, J. M.
Journal: J Med Chem

5-HT 1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT 1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT 1 receptor subtypes and providing new approaches for the treatment of depression.

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Spiro[(dihydropyrazin-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4 ',9'-dione)]-Based Cytotoxic Agents: Structure-Activity Relationship Studies on the Substituent at N4-Position of the Diketopiperazine Domain.

Publication Date: 2008 May 22 PMID: 18429610
Authors: Gomez-Monterrey, I. - Campiglia, P. - Carotenuto, A. - Stiuso, P. - Bertamino, A. - Sala, M. - Aquino, C. - Grieco, P. - Morello, S. - Pinto, A. - Ianelli, P. - Novellino, E.
Journal: J Med Chem

Analogues of the previously reported potent cytotoxic spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3- b]naphtho-4',9'-dione)] derivatives ( 3, 3') were prepared to explore new structural requirements at the diketopiperazine domain for the cytotoxic activity. The in vitro activity was evaluated against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines. The 4-[(2- N, N-dimethyl)amino]ethyl ( 6i), and the 4-(2-pyrrolydin)ethyl ( 6l) derivatives emerged as the most potent compounds of this series, with a cytotoxic activity comparable to that of doxorubicin. These compounds, in both racemic and pure enantiomeric forms, showed also a high efficacy in cell lines resistant to doxorubicin (MCF-7/Dx) and in cell lines that were highly resistant to treatment with doxorubicin, such as HEK-293 (kidney), M-14 (melanoma), and HeLa (cervical adenocarcinoma) human cell lines. In addition, the effects on growth and cell cycle progression in CaCo-2 cell line (colon adenocarcinoma) and DNA-binding properties were investigated.

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From the selective serotonin transporter inhibitor citalopram to the selective norepinephrine transporter inhibitor talopram: synthesis and structure-activity relationship studies.

Publication Date: 2008 May 22 PMID: 18429609
Authors: Eildal, J. N. - Andersen, J. - Kristensen, A. S. - Jorgensen, A. M. - Bang-Andersen, B. - Jorgensen, M. - Stromgaard, K.
Journal: J Med Chem

Citalopram and talopram are structurally closely related, but they have very distinct pharmacological profiles as selective inhibitors of the serotonin and norepinephrine transporters, respectively. A systematic structure-activity relationship study was performed, in which each of the four positions distinguishing the two compounds were varied. The inhibitory potencies of the resulting 16 compounds were tested at both serotonin and norepinephrine transporters. This showed that particularly two of the four positions are determinants for the biological activity.

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Discovery and Optimization of Triazolopyridazines as Potent and Selective Inhibitors of the c-Met Kinase.

Publication Date: 2008 May 22 PMID: 18426196
Authors: Albrecht, B. K. - Harmange, J. C. - Bauer, D. - Berry, L. - Bode, C. - Boezio, A. A. - Chen, A. - Choquette, D. - Dussault, I. - Fridrich, C. - Hirai, S. - Hoffman, D. - Larrow, J. F. - Kaplan-Lefko, P. - Lin, J. - Lohman, J. - Long, A. M. - Moriguchi, J. - O'Connor, A. - Potashman, M. H. - Reese, M. - Rex, K. - Siegmund, A. - Shah, K. - Shimanovich, R. - Springer, S. K. - Teffera, Y. - Yang, Y. - Zhang, Y. - Bellon, S. F.
Journal: J Med Chem

Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.

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Combination of Non-natural d-Amino Acid Derivatives and Allophenylnorstatine-Dimethylthioproline Scaffold in HIV Protease Inhibitors Have High Efficacy in Mutant HIV.

Publication Date: 2008 May 22 PMID: 18426195
Authors: Nakatani, S. - Hidaka, K. - Ami, E. - Nakahara, K. - Sato, A. - Nguyen, J. T. - Hamada, Y. - Hori, Y. - Ohnishi, N. - Nagai, A. - Kimura, T. - Hayashi, Y. - Kiso, Y.
Journal: J Med Chem

Several non-natural d-amino acid derivatives were introduced as P 2/P 3 residues in allophenylnorstatine-containing (Apns; (2 S,3 S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that d-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the d-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha 1-acid glycoprotein in the test medium.

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Synthesis, characterization, and metabolic stability of porphyrin-Peptide conjugates bearing bifunctional signaling sequences.

Publication Date: 2008 May 22 PMID: 18426194
Authors: Sibrian-Vazquez, M. - Jensen, T. J. - Vicente, M. G.
Journal: J Med Chem

A series of four porphyrin-peptide conjugates bearing one linear bifunctional sequence containing a cell penetrating peptide (CPP) and a nuclear localization signal (NLS) were synthesized and their in vitro biological and stability properties investigated. All conjugates accumulated within human HEp2 cells to a significantly higher extent than their porphyrin-PEG precursor, and the extent of their uptake and cytotoxicity depends on the nature and sequence of the amino acids. Conjugates 2 and 5 bearing a NLS-CPP accumulated the most within cells and were the most phototoxic (IC 50 approximately 7 microM at 1 J/cm (2)). All conjugates localized preferentially within the cell lysosomes, and in addition, conjugate 2 was also found in the ER. All conjugates were highly stable under nonenzymatic conditions, but their peptide sequences were cleaved to some extent (ca. 50% after 24 h) by proteolytic enzymes, such as cathepsin B, cathepsin D, prolidase, and plasmin.

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Synthesis and Biological Evaluation of Pyridazinone Analogues as Potential Cardiac Positron Emission Tomography Tracers.

Publication Date: 2008 May 22 PMID: 18422306
Authors: Purohit, A. - Radeke, H. - Azure, M. - Hanson, K. - Benetti, R. - Su, F. - Yalamanchili, P. - Yu, M. - Hayes, M. - Guaraldi, M. - Kagan, M. - Robinson, S. - Casebier, D.
Journal: J Med Chem

A series of fluorinated pyridazinone derivatives with IC 50 values ranging from 8 to 4000 nM for the mitochondrial complex 1 (MC1) have been prepared. Structure-activity relationship (SAR) assessment indicated preference of the fluorine label to be incorporated on an alkyl side chain rather than directly on the pyridazinone moiety. Tissue distribution studies of a series of analogues ([ (18)F] 22- 28) in Sprague-Dawley (SD) rats identified [ (18)F] 27 as the most promising radiotracer with high uptake in cardiac tissue (3.41%ID/g; 30 min post injection) in addition to favorable heart to nontarget organ distribution ratios. MicroPET images of SD rats and nonhuman primates after [ (18)F] 27 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.

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Effects of targeting moiety, linker, bifunctional chelator, and molecular charge on biological properties of (64)cu-labeled triphenylphosphonium cations.

Publication Date: 2008 May 22 PMID: 18419113
Authors: Kim, Y. S. - Yang, C. T. - Wang, J. - Wang, L. - Li, Z. B. - Chen, X. - Liu, S.
Journal: J Med Chem

In this report, we present the synthesis and evaluation of six new (64)Cu-labeled triphenylphosphonium (TPP) cations. Biodistribution studies were performed using the athymic nude mice bearing U87MG human glioma xenografts to explore the impact of TPP moieties, linkers, bifunctional chelators (BFCs), and molecular charge on biological properties of (64)Cu radiotracers. On the basis of the results from this study, it is concluded that (1) mTPP (tris(4-methoxyphenyl)phosphonium) is a better mitochondrion-targeting molecule than TPP and 3mTPP (tris(2,4,6-trimethoxyphenyl)phosphonium); (2) DO3A (1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid) and DO2A (1,4,7,10-tetraazacyclododecane-4,7-diacetic acid) are suitable BFCs for the (64)Cu-labeling of TPP cations; (3) NOTA-Bn ( S-2-(4-thioureidobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid) has a significant adverse effect on the radiotracer tumor uptake and tumor-to-background ratios; and (4) monoanionic BFCs should be avoided to ensure that (64)Cu chelate has a neutral or negative charge. Considering the tumor uptake and tumor/liver ratios, (64)Cu(DO2A-xy-TPP) (+) is the best candidate for more extensive evaluations in different tumor-bearing animal models.

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Non-Peptide Gonadotropin-Releasing Hormone Receptor Antagonists.

Publication Date: 2008 Apr 18 PMID: 18419112
Authors: Betz, S. F. - Zhu, Y. F. - Chen, C. - Struthers, R. S.
Journal: J Med Chem

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Straightforward recursive partitioning model for discarding insoluble compounds in the drug discovery process.

Publication Date: 2008 May 22 PMID: 18419111
Authors: Lamanna, C. - Bellini, M. - Padova, A. - Westerberg, G. - Maccari, L.
Journal: J Med Chem

Poor aqueous solubility is one of the major issues in drug discovery and development, impacting negatively on all aspects of the research and development process. The pharmaceutical industry has realized that solubility issues need to be resolved at the discovery stage. We here present an innovative way to address this problem via a model designed to address the simple question, "Is the compound likely to be sufficiently soluble to provide interpretable data in biological screening assays?" A recursive partitioning (RP) method was applied to a set of 3563 molecules, with in house determined aqueous solubility values. Five models were generated on the basis of a small number of descriptors affording intuitive information regarding structural features influencing solubility. The final model was based on only two descriptors: the molecular weight (MW) and the aromatic proportion (AP). This model provided satisfactory values of accuracy (81%) and precision (75%) for a test set of 1200 compounds, suggesting that the model may add value in compound selection and library design during early drug discovery.

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Thiocamptothecin.

Publication Date: 2008 May 22 PMID: 18419110
Authors: Samori, C. - Guerrini, A. - Varchi, G. - Zunino, F. - Beretta, G. L. - Femoni, C. - Bombardelli, E. - Fontana, G. - Battaglia, A.
Journal: J Med Chem

The synthesis and the X-ray structure of 16a-thiocamptothecin (TCPT), the thiopyridone analog of camptothecin (CPT), are accomplished. The crystal contains two structurally identical, yet independent molecules. Both of them are connected to other molecules via two intermolecular hydrogen bonds. S-Methylation of TCPT leads to the cleavage of the C-ring. The cytotoxic activity of TCPT was evaluated against different human tumor cell lines using CPT as reference compound.

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Benzofuran-based hybrid compounds for the inhibition of cholinesterase activity, Beta amyloid aggregation, and abeta neurotoxicity.

Publication Date: 2008 May 22 PMID: 18419109
Authors: Rizzo, S. - Riviere, C. - Piazzi, L. - Bisi, A. - Gobbi, S. - Bartolini, M. - Andrisano, V. - Morroni, F. - Tarozzi, A. - Monti, J. P. - Rampa, A.
Journal: J Med Chem

The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multitarget strategies to combat causes and symptoms. We therefore designed, synthesized, and tested new hybrid molecules linking a benzofuran ring to a N-methyl- N-benzylamine through a heptyloxy chain, affording a series of potential multifunctional drugs for AD. The cholinesterase inhibitory activity was extended to the inhibition of Abeta fibril formation for 1, 3, and 5. Compound 3 showed an additional neuroprotective effect.

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2-Amino-1,3-thiazol-4(5H)-ones as Potent and Selective 11beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitors: Enzyme-Ligand Co-Crystal Structure and Demonstration of Pharmacodynamic Effects in C57Bl/6 Mice.

Publication Date: 2008 May 22 PMID: 18419108
Authors: Johansson, L. - Fotsch, C. - Bartberger, M. D. - Castro, V. M. - Chen, M. - Emery, M. - Gustafsson, S. - Hale, C. - Hickman, D. - Homan, E. - Jordan, S. R. - Komorowski, R. - Li, A. - McRae, K. - Moniz, G. - Matsumoto, G. - Orihuela, C. - Palm, G. - Veniant, M. - Wang, M. - Williams, M. - Zhang, J.
Journal: J Med Chem

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has attracted considerable attention during the past few years as a potential target for the treatment of diseases associated with metabolic syndrome. In our ongoing work on 11beta-HSD1 inhibitors, a series of new 2-amino-1,3-thiazol-4(5 H)-ones were explored. By inserting various cycloalkylamines at the 2-position and alkyl groups or spirocycloalkyl groups at the 5-position of the thiazolone, several potent 11beta-HSD1 inhibitors were identified. An X-ray cocrystal structure of human 11beta-HSD1 with compound 6d ( K i = 28 nM) revealed a large lipophilic pocket accessible by substitution off the 2-position of the thiazolone. To increase potency, analogues were prepared with larger lipophilic groups at this position. One of these compounds, the 3-noradamantyl analogue 8b, was a potent inhibitor of human 11beta-HSD1 ( K i = 3 nM) and also inhibited 11beta-HSD1 activity in lean C57Bl/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.

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In Vitro and In Vivo Evaluation of Bifunctional Bisthiosemicarbazone (64)Cu-Complexes for the Positron Emission Tomography Imaging of Hypoxia.

Publication Date: 2008 May 22 PMID: 18416544
Authors: Bonnitcha, P. D. - Vavere, A. L. - Lewis, J. S. - Dilworth, J. R.
Journal: J Med Chem

The copper(II) bisthiosemicarbazonato complex, copper-diacetyl-bis( N (4)-methylthiosemicarbazonate) (Cu-ATSM), has been used clinically as a positron emission tomography (PET) tracer for the delineation of hypoxia. Six novel, asymmetric bis(thiosemicarbazones) derived from diacetyl-2-(4- N-methyl-3-thiosemicarbazone)-3-(4- N-amino-3-thiosemicarbazone) (H 2ATSM/A), one of which contained a nitroimidazole functionality, were radiolabeled with (64)Cu ( t (1/2) = 12.7 h, beta+ = 19.3%). In vitro studies were performed on three of the compounds using EMT6 mammary carcinoma cells under hypoxic and normoxic conditions. All compounds displayed rapid cellular association and appreciable hypoxic selectivity with increased uptake under normoxic and hypoxic conditions when compared to (64)Cu-ATSM. Biodistribution and small animal PET imaging studies were then carried out in vivo using two compounds in EMT6 tumor-bearing mice. The compounds showed high tumor uptake, but also substantial accumulation in the liver. These complexes demonstrate that H 2ATSM/A represents a novel and versatile synthetic platform that can be utilized to provide hypoxic cell selectivity through functionalization of the bisthiosemicarbazonate group.

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Aza-peptidyl Michael Acceptors. A New Class of Potent and Selective Inhibitors of Asparaginyl Endopeptidases (Legumains) from Evolutionarily Diverse Pathogens.

Publication Date: 2008 May 8 PMID: 18416543
Authors: Gotz, M. G. - James, K. E. - Hansell, E. - Dvorak, J. - Seshaadri, A. - Sojka, D. - Kopacek, P. - McKerrow, J. H. - Caffrey, C. R. - Powers, J. C.
Journal: J Med Chem

Aza-peptide Michael acceptors with the general structure of Cbz-Ala-Ala-AAsn- trans-CHCHCOR are a new class of inhibitors specific for the asparaginyl endopeptidases (AE) (legumains). Structure-activity relationships (SARs) were characterized for a set of 31 aza-peptide Michael acceptors with AEs derived from three medically important parasites: the protist Trichomonas vaginalis, the hard tick Ixodes ricinus, and the flatworm Schistosoma mansoni. Despite arising from phylogenetically disparate organisms, all three AEs shared a remarkably similar SAR with lowest IC 50 values extending into the picomolar range. The results suggest an evolutionary constraint on the topography of the prime side of the active site. SAR also revealed that esters in the P1' position are more potent than disubstituted amides and that monosubstituted amides and alkyl derivatives show little or no inhibition. The preferred P1' residues have aromatic substituents. Aza-asparaginyl Michael acceptors react with thiols, which provides insight into the mechanism of their inhibition of asparaginyl endopeptidases.

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Computational chemistry publications in the journal of medicinal chemistry.

Publication Date: 2008 Apr 24 PMID: 18416523
Authors: Bajorath, J.
Journal: J Med Chem

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Structural Origin of Selectivity in Class II-Selective Histone Deacetylase Inhibitors.

Publication Date: 2008 May 22 PMID: 18412327
Authors: Estiu, G. - Greenberg, E. - Harrison, C. B. - Kwiatkowski, N. P. - Mazitschek, R. - Bradner, J. E. - Wiest, O.
Journal: J Med Chem

The development of class- and isoform-selective histone deacetylase (HDAC) inhibitors is highly desirable for the study of the complex interactions of these proteins central to transcription regulation as well as for the development of selective HDAC inhibitors as drugs in epigenetics. To provide a structural basis for the rational design of such inhibitors, a combined computational and experimental study of inhibition of three different histone deacetylase isoforms, HDAC1, -6, and -8, with three different hydroxamate inhibitors is reported. While SAHA was found to be unselective for the inhibition of class I and class II HDACs, the other inhibitors were found to be selective toward class II HDACs. Molecular dynamics simulations indicate that this selectivity is caused by both the overall shape of the protein surface leading to the active site and specific interactions of an aspartate residue in a polar loop and two phenylalanines and a methionine in a nonpolar loop. Monitoring the specific interactions as a function of the simulation time identifies a key sulfur-pi interaction. The implications of the structural motifs for the design of class II-selective HDAC inhibitors are discussed.

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Novel Potent and Selective Thrombin Inhibitors Based on a Central 1,4-Benzoxazin-3(4H)-one Scaffold.

Publication Date: 2008 May 8 PMID: 18412326
Authors: Ilas, J. - Tomasic, T. - Kikelj, D.
Journal: J Med Chem

Novel thrombin inhibitors with the central 1,4-benzoxazine-3(4 H)-one scaffold, benzamidine P 1 arginine side chain mimetic and various P 3 moieties are described. 3-(Benzyl(2-(4-carbamimidoylbenzyl)-4-methyl-3-oxo-3,4-dihydro-2 H-1,4-benzoxazin-7-yl)amino)-3-oxopropanoic acid ( 7b), the most potent compound in the series, exhibited a K i of 2.6 nM in vitro for thrombin and high selectivity against trypsin and factor Xa.

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Degradation of Bidentate-Coordinated Platinum(II)-Based DNA Intercalators by Reduced l-Glutathione.

Publication Date: 2008 May 8 PMID: 18412325
Authors: Kemp, S. - Wheate, N. J. - Pisani, M. J. - Aldrich-Wright, J. R.
Journal: J Med Chem

We have examined the interaction of [(5,6-dimethyl-1,10-phenanthroline)(1 S,2 S-diaminocyclohexane)platinum(II)] (2+) ( 1, 56MESS), [(5-methyl-1,10-phenanthroline)(1 S,2 S-diaminocyclohexane)platinum(II)] (2+) ( 2, 5MESS), [(5,6-dimethyl-1,10-phenanthroline)(1 R,2 R-diaminocyclohexane)platinum(II)] (2+) ( 3, 56MERR), and [(5,6-dimethyl-1,10-phenanthroline)(ethylenediamine)platinum(II)] (2+) ( 4, 56MEEN) with reduced l -glutathione and l -methionine. Both thiols degrade all four complexes, mainly by displacing the ancillary ligand and forming a doubly bridged dinuclear complex. The degradation half-life of all the complexes with methionine is >7 days, indicating that these reactions are not biologically relevant. The rate of degradation by glutathione appears to be particularly important and shows an inverse correlation to cytotoxicity. The least active complex, 4 ( t 1/2 glutathione: 20 h), degrades fastest, followed by 3 (31 h), 2 (40 h), and 1 (68 h). The major degradation product, [bis-mu-{reduced l -glutathione}bis{5,6-dimethyl-1,10-phenanthroline}bis{platinum(II)}] (2+) ( 5, 56MEGL), displays no cytotoxicity and is excluded as the source of the anticancer activity. Once bound by glutathione, these metal complexes do not then form coordinate bonds with guanosine. Partial encapsulation of the complexes within cucurbit[ n]urils is able to stop the degradation process.

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Synthesis and Screening of Mono- and Di-Aryl Technetium and Rhenium Metallocarboranes. A New Class of Probes for the Estrogen Receptor.

Publication Date: 2008 May 8 PMID: 18412324
Authors: Causey, P. W. - Besanger, T. R. - Valliant, J. F.
Journal: J Med Chem

A series of mono and diaryl rhenium(I)-carborane derivatives were prepared using microwave heating and screened for their affinity for two isoforms of the estrogen receptor (ER). The rhenacarborane derivative [(RR'C 2B 9H 9)Re(CO) 3] (-) (R = p-PhOH, R' = H), which was generated by taking advantage of a recently discovered cage isomerization process, and the neutral nitrosated analogue [(RR'C 2B 9H 9)Re(CO) 2(NO)] (R = p-PhOH, R' = H) showed the highest affinities of the compounds screened. As a result, the (99m)Tc analogue of one of the leads was produced in high yield (84%) and specific activity in a manner that is suitable for routine production in support of future preclinical and molecular imaging studies.

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Book review of modern biooxidation. Enzymes, reactions and applications.

Publication Date: 2008 May 22 PMID: 18412323
Authors: Walters, D. E.
Journal: J Med Chem

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Design and synthesis of conformationally constrained glucagon-like Peptide-1 derivatives with increased plasma stability and prolonged in vivo activity.

Publication Date: 2008 May 8 PMID: 18412318
Authors: Miranda, L. P. - Winters, K. A. - Gegg, C. V. - Patel, A. - Aral, J. - Long, J. - Zhang, J. - Diamond, S. - Guido, M. - Stanislaus, S. - Ma, M. - Li, H. - Rose, M. J. - Poppe, L. - Veniant, M. M.
Journal: J Med Chem

A series of conformationally constrained derivatives of glucagon-like peptide-1 (GLP-1) were designed and evaluated. By use of [Gly (8)]GLP-1(7-37)-NH 2 ( 2) peptide as a starting point, 17 cyclic derivatives possessing i to i + 4, i to i + 5, or i to i + 7 side chain to side chain lactam bridges from positions 18 to 30 were prepared. The effect of a helix-promoting alpha-amino-isobutyric acid (Aib) substitution at position 22 was also evaluated. The introduction of i to i + 4 glutamic acid-lysine lactam constraints in c[Glu (18)-Lys (22)][Gly (8)]GLP-1(7-37)-NH 2 ( 6), c[Glu (22)-Lys (26)][Gly (8)]GLP-1(7-37) -NH 2 ( 10), and c[Glu (23)-Lys (27)][Gly (8)]GLP-1(7-37) -NH 2 ( 11) resulted in potent functional activity and receptor affinities comparable to native GLP-1. Selected GLP-1 peptides were chemoselectively PEGylated in order to prolong their in vivo activity. PEGylated peptides [Gly (8),Aib (22)]GLP-1(7-37) -Cys ((PEG))-Ala-NH 2 ( 23) and c[Glu (22)-Lys (26)][Gly (8)]GLP-1(7-37)-Cys ((PEG))-Ser-Gly -NH 2 ( 24) retained picomolar functional potency and avid receptor binding properties. Importantly, PEGylated GLP-1 peptide 23 exhibited sustained in vivo efficacy with respect to blood glucose reduction and decreased body weight for several days in nonhuman primates.

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(3R,5S,E)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-tr iazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with Reduced Myotoxicity Potential.

Publication Date: 2008 May 8 PMID: 18412317
Authors: Ahmad, S. - Madsen, C. S. - Stein, P. D. - Janovitz, E. - Huang, C. - Ngu, K. - Bisaha, S. - Kennedy, L. J. - Chen, B. C. - Zhao, R. - Sitkoff, D. - Monshizadegan, H. - Yin, X. - Ryan, C. S. - Zhang, R. - Giancarli, M. - Bird, E. - Chang, M. - Chen, X. - Setters, R. - Search, D. - Zhuang, S. - Nguyen-Tran, V. - Cuff, C. A. - Harrity, T. - Darienzo, C. J. - Li, T. - Reeves, R. A. - Blanar, M. A. - Barrish, J. C. - Zahler, R. - Robl, J. A.
Journal: J Med Chem

3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

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Design and Microwave-Assisted Synthesis of Novel Macrocyclic Peptides Active at Melanocortin Receptors: Discovery of Potent and Selective hMC5R Receptor Antagonists.

Publication Date: 2008 May 8 PMID: 18412316
Authors: Grieco, P. - Cai, M. - Liu, L. - Mayorov, A. - Chandler, K. - Trivedi, D. - Lin, G. - Campiglia, P. - Novellino, E. - Hruby, V. J.
Journal: J Med Chem

Differentiation of the physiological role of the melanocortin receptor 5 MC5R from that of other melanocortin receptors will require development of high affinity and selective antagonists. To date, a few synthetic antagonist ligands active at hMC5 receptor are available, but most do not have appreciable selectivity. With the aim to gain more potent and selective antagonists for the MC5R ligands, we have designed, synthesized, and pharmacologically characterized a series of alkylthioaryl-bridged macrocyclic peptide analogues derived from MT-II and SHU9119. These 20-membered macrocycles were synthesized by a tandem combination using solid phase peptide synthesis and microwave-assisted reactions. Biological assays for binding affinities and adenylate cyclase activities for the hMC1R, hMC3R, hMC4R, and hMC5R showed that three analogues, compounds, 9, 4, and 7, are selective antagonists at the hMC5 receptor. In particular, compound 9(PG-20N) is a selective and competitive hMC5R antagonist, with IC 50 of 130 +/- 11 nM, and a pA 2 value of 8.3, and represents an important tool for further biological investigations of the hMC5R. Compounds 4 and 7 (PG14N, PG17N) show potent and selective allosteric inhibition at hMC5R with IC 50 values of 38 +/- 3 nM and 58 +/- 6 nM, respectively. Compound 9 will be used to further investigate and more clearly understand the physiological roles played by the MC5 receptor in humans and other animals.

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Combining Docking, Molecular Dynamics and the Linear Interaction Energy Method to Predict Binding Modes and Affinities for Non-nucleoside Inhibitors to HIV-1 Reverse Transcriptase.

Publication Date: 2008 May 8 PMID: 18410085
Authors: Carlsson, J. - Boukharta, L. - Aqvist, J.
Journal: J Med Chem

Docking, scoring, molecular dynamics (MD), and the linear interaction energy (LIE) method are used here to predict binding modes and affinities for a set of 43 non-nucleoside inhibitors to HIV-1 reverse transcriptase. Starting from a crystallographic structure, the binding modes of 43 inhibitors are predicted using automated docking. The Goldscore scoring function and the LIE method are then used to determine the relative binding free energies for the inhibitors. The Goldscore scoring function does not reproduce the relative binding affinities for the inhibitors, while the standard parametrization of the LIE method reproduces the experimental binding free energies for 39 inhibitors with an R (2) = 0.70 and an unsigned average error of 0.8 kcal/mol. The present calculations provide a validation of the combination of docking, MD, and LIE as a powerful tool in structure-based drug design, and the methodology is easily scalable for attaining a higher throughput of compounds.

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Ring Size of Somatostatin Analogues (ODT-8) Modulates Receptor Selectivity and Binding Affinity.

Publication Date: 2008 May 8 PMID: 18410084
Authors: Erchegyi, J. - Grace, C. R. - Samant, M. - Cescato, R. - Piccand, V. - Riek, R. - Reubi, J. C. - Rivier, J. E.
Journal: J Med Chem

The synthesis, biological testing, and NMR studies of several analogues of H-c[Cys (3)-Phe (6)-Phe (7)-DTrp (8)-Lys (9)-Thr (10)-Phe (11)-Cys (14)]-OH (ODT-8, a pan-somatostatin analogue, 1) have been performed to assess the effect of changing the stereochemistry and the number of atoms in the disulfide bridge on binding affinity. Cysteine at positions 3 and/or 14 (somatostatin numbering) were/was substituted with d-cysteine, norcysteine, d-norcysteine, homocysteine, and/or d-homocysteine. The 3D structure analysis of selected partially selective, bioactive analogues ( 3, 18, 19, and 21) was carried out in dimethylsulfoxide. Interestingly and not unexpectedly, the 3D structures of these analogues comprised the pharmacophore for which the analogues had the highest binding affinities (i.e., sst 4 in all cases).

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Ring Size in Octreotide Amide Modulates Differently Agonist versus Antagonist Binding Affinity and Selectivity.

Publication Date: 2008 May 8 PMID: 18410083
Authors: Grace, C. R. - Erchegyi, J. - Samant, M. - Cescato, R. - Piccand, V. - Riek, R. - Reubi, J. C. - Rivier, J. E.
Journal: J Med Chem

H-DPhe (2)-c[Cys (3)-Phe (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Thr (15)-NH 2 ( 1) (a somatostatin agonist, SRIF numbering) and H-Cpa (2)-c[DCys (3)-Tyr (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Nal (15)-NH 2 ( 4) (a somatostatin antagonist) are based on the structure of octreotide that binds to three somatostatin receptor subtypes (sst 2/3/5) with significant binding affinity. Analogues of 1 and 4 were synthesized with norcysteine (Ncy), homocysteine (Hcy), or d-homocysteine (DHcy) at positions 3 and/or 14. Introducing Ncy at positions 3 and 14 constrained the backbone flexibility, resulting in loss of binding affinity at all sst s. The introduction of Hcy at positions 3 and 14 improved selectivity for sst 2 as a result of significant loss of binding affinity at the other sst s. Substitution by DHcy at position 3 in the antagonist scaffold ( 5), on the other hand, resulted in a significant loss of binding affinity at sst 2 and sst 3 as compared to the different affinities of the parent compound ( 4). The 3D NMR structures of the analogues in dimethylsulfoxide are consistent with the observed binding affinities.

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Identification of Plasmodium falciparum Spermidine Synthase Active Site Binders through Structure-Based Virtual Screening.

Publication Date: 2008 May 8 PMID: 18410081
Authors: Jacobsson, M. - Garedal, M. - Schultz, J. - Karlen, A.
Journal: J Med Chem

Seven novel binders, binding in the active site of Plasmodium falciparum spermidine synthase, were identified by structure-based virtual screening. The binding of these compounds was experimentally verified by NMR techniques. Spermidine synthase, an enzyme involved in the polyamine pathway, has been suggested as a target for treating malaria. The virtual screening protocol combined 3D pharmacophore filtering, docking, and scoring, focusing on finding compounds predicted to form interactions mimicking those of a previously known binder. The virtual screen resulted in the selection of 28 compounds that were acquired and tested from 2.6 million starting structures. Two of the seven binders were predicted to bind in the amino substrate binding pocket. Both of these showed stronger binding upon addition of methylthioadenosine, one of the two products of the enzyme, and a known binder and inhibitor. The five other compounds were predicted to bind in the part of the active site where the other substrate, decarboxylated S-adenosylmethionine, binds. These five compounds all competed for binding with methylthioadenosine.

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Predicting binding modes from free energy calculations.

Publication Date: 2008 May 8 PMID: 18410080
Authors: Nervall, M. - Hanspers, P. - Carlsson, J. - Boukharta, L. - Aqvist, J.
Journal: J Med Chem

To produce reliable predictions of bioactive conformations is a major challenge in the field of structure-based inhibitor design and is a requirement for accurate binding free energy predictions with structure-based methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal structure that resulted in two distinct clusters of possible conformations. One of these clusters was compatible with an existing crystal structure, whereas the other displayed a flipped heterocyclic group. Binding free energies, using the non-native crystal structure, calculated from several scoring functions, were similar for the two clusters, and no conclusion about the binding mode could be drawn from these results. The two clusters could be separated through rescoring with the linear interaction method (LIE) in combination with molecular dynamics simulations, which leads to a binding mode prediction in line with experimental crystallographic data. Further, the LIE model produces the best correlation between experimental and calculated binding free energies among the tested scoring methods.

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Discovery of Subnanomolar Arginine-Glycine-Aspartate-Based alphaVbeta3/alphaVbeta5 Integrin Binders Embedding 4-Aminoproline Residues.

Publication Date: 2008 May 8 PMID: 18402433
Authors: Zanardi, F. - Burreddu, P. - Rassu, G. - Auzzas, L. - Battistini, L. - Curti, C. - Sartori, A. - Nicastro, G. - Menchi, G. - Cini, N. - Bottoncetti, A. - Raspanti, S. - Casiraghi, G.
Journal: J Med Chem

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Structural Determinants for Affinity Enhancement of a Dual Antagonist Peptide Entry Inhibitor of Human Immunodeficiency Virus Type-1.

Publication Date: 2008 May 8 PMID: 18402432
Authors: Gopi, H. - Umashankara, M. - Pirrone, V. - Lalonde, J. - Madani, N. - Tuzer, F. - Baxter, S. - Zentner, I. - Cocklin, S. - Jawanda, N. - Miller, S. R. - Schon, A. - Klein, J. C. - Freire, E. - Krebs, F. C. - Smith, A. B. - Sodroski, J. - Chaiken, I.
Journal: J Med Chem

Structure-activity correlations were investigated for substituted peptide conjugates that function as dual receptor site antagonists of HIV-1 gp120. A series of peptide conjugates were constructed via click reaction of both aryl and alkyl acetylenes with an internally incorporated azidoproline 6 derived from the parent peptide 1 (12p1, RINNIPWSEAMM). Compared to 1, many of these conjugates were found to exhibit several orders of magnitude increase in both affinity for HIV-1 gp120 and inhibition potencies at both the CD4 and coreceptor binding sites of gp120. We sought to determine structural factors in the added triazole grouping responsible for the increased binding affinity and antiviral activity of the dual inhibitor conjugates. We measured peptide conjugate potencies in both kinetic and cell infection assays. High affinity was sterically specific, being exhibited by the cis- but not the trans-triazole. The results demonstrate that aromatic, hydrophobic, and steric features in the residue 6 side-chain are important for increased affinity and inhibition. Optimizing these features provides a basis for developing gp120 dual inhibitors into peptidomimetic and increasingly smaller molecular weight entry antagonist leads.

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Comparing In Vitro and In Vivo Activity of 2'-O-[2-(Methylamino)-2-oxoethyl]- and 2'-O-Methoxyethyl-Modified Antisense Oligonucleotides.

Publication Date: 2008 May 8 PMID: 18399648
Authors: Prakash, T. P. - Kawasaki, A. M. - Wancewicz, E. V. - Shen, L. - Monia, B. P. - Ross, B. S. - Bhat, B. - Manoharan, M.
Journal: J Med Chem

A number of 2'- O-modified antisense oligonucleotides have been reported for their potential use in oligonucleotide-based therapeutics. To date, most of the in vivo data has been generated for 2'- O-MOE (2'- O-methoxyethyl)- and 2'- O-Me (2'- O-methyl)-modified ASOs (antisense oligonucleotides). We now report the synthesis and biological activity of another 2'- O-modification, namely 2'- O-[2-(methylamino)-2-oxoethyl] (2'- O-NMA). This modification resulted in an increase in the affinity of antisense oligonucleotides to complementary RNA similar to 2'- O-MOE-modified ASOs as compared to first-generation antisense oligodeoxynucleotides. The ASO modified with 2'- O-NMA reduced expression of PTEN mRNA in vitro and in vivo in a dose-dependent manner similar to 2'- O-MOE modified ASO. Importantly, toxicity parameters such as AST, ALT, organ weights, and body weights were found to be normal similar to 2'- O-MOE ASO-treated animal models. The data generated in these experiments suggest that 2'- O-NMA is a useful modification for potential application in both antisense and other oligonucleotide-based drug discovery efforts.

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Synthesis and biological activity of fluorinated combretastatin analogues.

Publication Date: 2008 May 8 PMID: 18396857
Authors: Alloatti, D. - Giannini, G. - Cabri, W. - Lustrati, I. - Marzi, M. - Ciacci, A. - Gallo, G. - Tinti, M. O. - Marcellini, M. - Riccioni, T. - Guglielmi, M. B. - Carminati, P. - Pisano, C.
Journal: J Med Chem

With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.

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Book review of iminosugars: from synthesis to therapeutic applications.

Publication Date: 2008 May 8 PMID: 18396856
Authors: Filer, C. N.
Journal: J Med Chem

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Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials.

Publication Date: 2008 May 8 PMID: 18396855
Authors: Yeates, C. L. - Batchelor, J. F. - Capon, E. C. - Cheesman, N. J. - Fry, M. - Hudson, A. T. - Pudney, M. - Trimming, H. - Woolven, J. - Bueno, J. M. - Chicharro, J. - Fernandez, E. - Fiandor, J. M. - Gargallo-Viola, D. - Gomez de Las Heras, F. - Herreros, E. - Leon, M. L.
Journal: J Med Chem

A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC 50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED 50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc 1 complex.

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Molecular characteristics for solid-state limited solubility.

Publication Date: 2008 May 22 PMID: 18396854
Authors: Wassvik, C. M. - Holmen, A. G. - Draheim, R. - Artursson, P. - Bergstrom, C. A.
Journal: J Med Chem

Solubility and solid-state characteristics were determined and multivariate data analysis was used to deduce structural features important for solid-state limited solubility of marketed drugs. Molecules with extended ring structures and large conjugated systems were less soluble, indicating that structural features related to rigidity and aromaticity result in solubility restricted by stable crystal structures. These descriptors successfully predicted the applied test set and can be useful for avoiding synthesis of compounds behaving like "brick dust".

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Synthesis of indoleamine 2,3-dioxygenase inhibitory analogues of the sponge alkaloid exiguamine a.

Publication Date: 2008 May 8 PMID: 18393489
Authors: Carr, G. - Chung, M. K. - Mauk, A. G. - Andersen, R. J.
Journal: J Med Chem

Synthetic analogues of the sponge natural product exiguamine A ( 3) have been prepared and evaluated for their ability to inhibit indoleamine 2,3-dioxygenase in vitro.

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Synthesis and Pharmacological Evaluations of Sildenafil Analogues for Treatment of Erectile Dysfunction.

Publication Date: 2008 May 8 PMID: 18393409
Authors: Flores Toque, H. A. - Priviero, F. B. - Teixeira, C. E. - Perissutti, E. - Fiorino, F. - Severino, B. - Frecentese, F. - Lorenzetti, R. - Baracat, J. S. - Santagada, V. - Caliendo, G. - Antunes, E. - De Nucci, G.
Journal: J Med Chem

The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1, 6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues ( 6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC 50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC 50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.

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Book review of drug metabolism in drug design and development.

Publication Date: 2008 May 8 PMID: 18393408
Authors: Jones, J. P.
Journal: J Med Chem

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Genome mining for novel natural product discovery.

Publication Date: 2008 May 8 PMID: 18393407
Authors: Challis, G. L.
Journal: J Med Chem

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Combinatorial biosynthesis of natural products.

Publication Date: 2008 May 8 PMID: 18393406
Authors: Zhang, W. - Tang, Y.
Journal: J Med Chem

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Natural products, small molecules, and genetics in tuberculosis drug development.

Publication Date: 2008 May 8 PMID: 18393405
Authors: Gutierrez-Lugo, M. T. - Bewley, C. A.
Journal: J Med Chem

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New strategies and methods in the discovery of natural product anti-infective agents: the mannopeptimycins.

Publication Date: 2008 May 8 PMID: 18393404
Authors: Koehn, F. E.
Journal: J Med Chem

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Chemical genetics: exploring the role of the proteasome in cell biology using natural products and other small molecule proteasome inhibitors.

Publication Date: 2008 May 8 PMID: 18393403
Authors: Kim, K. B. - Crews, C. M.
Journal: J Med Chem

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Natural products as leads to potential drugs: an old process or the new hope for drug discovery?

Publication Date: 2008 May 8 PMID: 18393402
Authors: Newman, D. J.
Journal: J Med Chem

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Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters.

Publication Date: 2008 May 8 PMID: 18393401
Authors: Hsin, L. W. - Chang, L. T. - Rothman, R. B. - Dersch, C. M. - Jacobson, A. E. - Rice, K. C.
Journal: J Med Chem

Novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp (2) hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted ( S)- 10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted ( R)- 8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT.

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Modern natural products chemistry and drug discovery.

Publication Date: 2008 May 8 PMID: 18393400
Authors: Ojima, I.
Journal: J Med Chem

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De Novo Design of Nonpeptidic Compounds Targeting the Interactions between Interferon-alpha and its Cognate Cell Surface Receptor.

Publication Date: 2008 May 8 PMID: 18393399
Authors: Bello, A. M. - Bende, T. - Wei, L. - Wang, X. - Majchrzak-Kita, B. - Fish, E. N. - Kotra, L. P.
Journal: J Med Chem

Type 1 interferons (IFN) bind specifically to the corresponding receptor, IFNAR. Agonists and antagonists for IFNAR have potential therapeutic value in the treatment of viral infections and systemic lupus erythematosus, respectively. Specific sequences on the surface of IFN, IFN receptor recognition peptides (IRRPs) mediate the binding and signal transduction when IFN interacts with IFNAR. Structural features of two such IRRPs, IRRP-1 and IRRP-3, were used as templates to design small molecule mimetics. In silico screening was used to identify the molecular structural features mimicking their surface characteristics. A set of 26 compounds were synthesized and their ability to interfere with IFN-IFNAR interactions was investigated. Two compounds exhibited antagonist activity, specifically, blocking IFN-inducible Stat phosphorylation Stat complex-DNA binding. Design principles revealed here pave the way toward a novel series of small molecules as antagonists for IFN-IFNAR interactions.

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Book review of drug discovery and development. Volume 2. Drug development.

Publication Date: 2008 May 8 PMID: 18393398
Authors: Wolff, M. E.
Journal: J Med Chem

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Chemical fragments as foundations for understanding target space and activity prediction.

Publication Date: 2008 May 8 PMID: 18386916
Authors: Sutherland, J. J. - Higgs, R. E. - Watson, I. - Vieth, M.
Journal: J Med Chem

The use of small inhibitors' fragment frequencies for understanding kinase potency and selectivity is described. By quantification of differences in the frequency of occurrence of fragments, similarities between small molecules and their targets can be determined. Naive Bayes models employing fragments provide highly interpretable and reliable means for predicting potency in individual kinases, as demonstrated in retrospective tests and prospective selections that were subsequently screened. Statistical corrections for prospective validation allowed us to accurately estimate success rates in the prospective experiment. Selectivity relationships between kinase targets are substantially explained by differences in the fragment composition of actives. By application of fragment similarities to the broader proteome, it is shown that targets related by sequence exhibit similar fragment preferences in small molecules. Of greater interest, certain targets unrelated by sequence are shown to have similar fragment preferences, even when the chemical similarity of ligands active at each target is low.

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