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The Discovery of Asunaprevir (BMS-650032), An Orally Efficacious NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

2014; American Chemical Society; Volume: 57; Issue: 5 Linguagem: Inglês

10.1021/jm500297k

1520-4804

Paul M. Scola, Li‐Qiang Sun, Alan Xiangdong Wang, Jie Chen, Ny Sin, Brian L. Venables, Sing‐Yuen Sit, Yan Chen, Anthony J. Cocuzza, Donna M. Bilder, Stanley V. D’Andrea, Barbara Zheng, Piyasena Hewawasam, Yong Qiang Tu, Jacques Friborg, Paul Falk, Dennis Hernandez, Steven M. LeVine, Chaoqun Chen, Fei Yu, Amy K. Sheaffer, Guangzhi Zhai, Diana Barry, Jay O. Knipe, Yong‐Hae Han, Richard Schartman, Maria Donoso, Kathy Mosure, Michael Sinz, Tatyana Zvyaga, Andrew C. Good, Ramkumar Rajamani, Kevin Kish, Jeffrey Tredup, Herbert E. Klei, Qi Gao, Luciano Mueller, Richard J. Colonno, Dennis M. Grasela, Stephen P. Adams, James Loy, Paul Lévesque, Huabin Sun, Hong Shi, Lucy Sun, William Warner, Danshi Li, Jialong Zhu, Nicholas A. Meanwell, Fiona McPhee,

Biochemical and Molecular Research

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).