The Discovery of Asunaprevir (BMS-650032), An Orally Efficacious NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
| Autor: | Danshi Li, Herbert E. Klei, Sing-Yuen Sit, Piyasena Hewawasam, Ny Sin, Brian Lee Venables, Paul Levesque, Qi Gao, Bilder Donna M, Dennis M. Grasela, Dennis Hernandez, Anthony J. Cocuzza, Amy K. Sheaffer, Richard J. Colonno, Jeffrey Tredup, Kathy Mosure, Stanley D'andrea, Jialong Zhu, Lucy Sun, Fei Yu, Paul Falk, Alan Xiangdong Wang, Steven Levine, Fiona McPhee, Andrew C. Good, Huabin Sun, Jay O. Knipe, Barbara Zheng, Richard Schartman, Nicholas A. Meanwell, Jie Chen, Maria Donoso, James Loy, Guangzhi Zhai, Ramkumar Rajamani, Li-Qiang Sun, Stephen P. Adams, Luciano Mueller, Tatyana Zvyaga, Yong Tu, Hong Shi, Paul Michael Scola, Chaoqun Chen, William Warner, Yan Chen, Yong-Hae Han, Diana Barry, Jacques Friborg, Kevin Kish, Michael Sinz |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Hepatitis C virus Phases of clinical research Viral Nonstructural Proteins Biology Pharmacology medicine.disease_cause Antiviral Agents chemistry.chemical_compound Dogs Drug Discovery medicine Animals Humans Protease Inhibitors Protease inhibitor (pharmacology) Beclabuvir Sulfonamides NS3 Isoquinolines Hepatitis C Virology Rats Discontinuation Clinical trial chemistry Molecular Medicine Asunaprevir Rabbits |
| Zdroj: | Journal of Medicinal Chemistry. 57:1730-1752 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm500297k |
| Popis: | The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24). |
| Databáze: | OpenAIRE |
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