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

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• 作者：Paul M. Scola ; Li-Qiang Sun ; Alan Xiangdong Wang ; Jie Chen ; Ny Sin ; Brian L. Venables ; Sing-Yuen Sit ; Yan Chen ; Anthony Cocuzza ; Donna M. Bilder ; Stanley V. D鈥橝ndrea ; Barbara Zheng ; Piyasena Hewawasam ; Yong Tu ; Jacques Friborg ; Paul Falk ; Dennis Hernandez ; Steven 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 W. 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 C. Levesque ; Huabin Sun ; Hong Shi ; Lucy Sun ; William Warner ; Danshi Li ; Jialong Zhu ; Nicholas A. Meanwell ; Fiona McPhee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1730-1752
• 全文大小：997K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

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鈥揳ctivity 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).