排序方式: 共有10条查询结果,搜索用时 15 毫秒
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Timothy A. Stammers René Coulombe Martin Duplessis Gulrez Fazal Alexandre Gagnon Michel Garneau Sylvie Goulet Araz Jakalian Steven LaPlante Jean Rancourt Bounkham Thavonekham Dominik Wernic George Kukolj Pierre L. Beaulieu 《Bioorganic & medicinal chemistry letters》2013,23(24):6879-6885
Optimization efforts on the anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors 1 and 2 resulted in the identification of multiple structural elements that contributed to improved cell culture potency. The additive effect of these elements resulted in compound 46, an inhibitor with enzymatic (IC50) and cell culture (EC50) potencies of less than 100 nanomolar. 相似文献
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Grace L. Jung Paul C. Anderson Murray Bailey Monique Baillet Gary W. Bantle Sylvie Berthiaume Pierre Lavallée Montse Llinas-Brunet Bounkham Thavonekham Diane Thibeault Bruno Simoneau 《Bioorganic & medicinal chemistry》1998,6(12):2317-2336
Renin inhibitors containing a 4,5- or a 3,5-dihydroxy-2-substituted-6-phenylhexanamide fragment at the P2---P3 sites have been prepared and evaluated. The four possible diastereomeric diols of the two series of inhibitors were synthesized to determine the optimal configuration of the carbinol centers for these replacements. The most potent inhibitors of each series, 1a and 2c have a molecular weight of only 503 and IC50 values of 23 and 20 nM in a human plasma renin assay at pH 6.0. Their very low aqueous solubility limited their further evaluation. The efficacy of these P2---P3 replacements is a result of their ability to maintain the important hydrogen-bonds with the enzyme. Due to conformational differences with the dipeptide, adjustment at the P2 side chain was required. These 4,5- and 3,5-dihydroxyhexanamide segments could be seen as novel N-terminal dipeptide replacements. 相似文献
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Yoakim C Bonneau PR Déziel R Doyon L Duan J Guse I Landry S Malenfant E Naud J Ogilvie WW O'Meara JA Plante R Simoneau B Thavonekham B Bös M Cordingley MG 《Bioorganic & medicinal chemistry letters》2004,14(3):739-742
A series of 8-heteroarylthiomethyldipyridodiazepinone derivatives were prepared and evaluated for their antiviral profile against wild type virus and the important K103N/Y181C mutant as an indicator for broad activity. 2,6-Dimethylpyridine derivative 16 was found to have a good pharmacokinetic profile in spite of poor metabolic stability in rat liver microsomes. 相似文献
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Timothy A. Stammers René Coulombe Jean Rancourt Bounkham Thavonekham Gulrez Fazal Sylvie Goulet Araz Jakalian Dominic Wernic Youla Tsantrizos Marc-André Poupart Michael Bös Ginette McKercher Louise Thauvette George Kukolj Pierre L. Beaulieu 《Bioorganic & medicinal chemistry letters》2013,23(9):2585-2589
A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a–c and 12a–c from a weak-binding fragment-like structure 1 as a starting point. 相似文献
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Claudio F. Sturino Yves Bousquet Clint A. James Patrick DeRoy Martin Duplessis Paul J. Edwards Ted Halmos Joannie Minville Louis Morency Sébastien Morin Bounkham Thavonekham Martin Tremblay Jianmin Duan Maria Ribadeneira Michel Garneau Alex Pelletier Sonia Tremblay Louie Lamorte Bruno Simoneau 《Bioorganic & medicinal chemistry letters》2013,23(13):3967-3975
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Pierre L. Beaulieu René Coulombe Jianmin Duan Gulrez Fazal Cédrickx Godbout Oliver Hucke Araz Jakalian Marc-André Joly Olivier Lepage Montse Llinàs-Brunet Julie Naud Martin Poirier Nathalie Rioux Bounkham Thavonekham George Kukolj Timothy A. Stammers 《Bioorganic & medicinal chemistry letters》2013,23(14):4132-4140
We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B–ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. 相似文献
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Pierre L. Beaulieu Eric Jolicoeur James Gillard Christian Brochu René Coulombe Nathalie Dansereau Jianmin Duan Michel Garneau Araz Jakalian Peter Kühn Lisette Lagacé Steven LaPlante Ginette McKercher Stéphane Perrault Martin Poirier Marc-André Poupart Timothy Stammers Louise Thauvette Bounkham Thavonekham George Kukolj 《Bioorganic & medicinal chemistry letters》2010,20(3):857-861
SAR studies at the N1-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC50 <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class. 相似文献
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Simoneau B Lavallée P Anderson PC Bailey M Bantle G Berthiaume S Chabot C Fazal G Halmos T Ogilvie WW Poupart MA Thavonekham B Xin Z Thibeault D Bolger G Panzenbeck M Winquist R Jung GL 《Bioorganic & medicinal chemistry》1999,7(3):489-508
A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development. 相似文献
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