Toward the Back-Up of Boceprevir (SCH 503034): Discovery of New Extended P4-Capped Ketoamide Inhibitors of Hepatitis C Virus NS3 Serine Protease with Improved Potency and Pharmacokinetic Pr

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• 作者：Stphane L. Bogen ; Weidong Pan ; Sumei Ruan ; Latha G. Nair ; Ashok Arasappan ; Frank Bennett ; Kevin X. Chen ; Edwin Jao ; Srikanth Venkatraman ; Bancha Vibulbhan ; Rong Liu ; Kuo-Chi Cheng ; Zhuyan Guo ; Xiao To
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：June 25, 2009
• 年：2009
• 卷：52
• 期：12
• 页码：3679-3688
• 全文大小：224K
• 年卷期：v.52,no.12(June 25, 2009)
• ISSN：1520-4804

文摘

Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P₄ pocket and optimization of the P₁′ capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P₄-capped inhibitors were also found to have improved PK profile.