Toward Second Generation Hepatitis C Virus NS3 Serine Protease Inhibitors: Discovery of Novel P4 Modified Analogues with Improved Potency and Pharmacokinetic Profile

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• 作者：Ashok Arasappan ; Angela I. Padilla ; Edwin Jao ; Frank Bennett ; Stephane L. Bogen ; Kevin X. Chen ; Russell E. Pike ; Mousumi Sannigrahi ; Joana Soares ; Srikanth Venkatraman ; Bancha Vibulbhan ; Anil K. Sakse
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：2806-2817
• 全文大小：229K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P′ secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.