Discovery and Structure−Activity Relationship of P1−P3 Ketoamide Derived Macrocyclic Inhibitors of Hepatitis C Virus NS3 Protease

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• 作者：Srikanth Venkatraman ; Francisco Velazquez ; Wanli Wu ; Melissa Blackman ; Kevin X. Chen ; Stephane Bogen ; Latha Nair ; Xiao Tong ; Robert Chase ; Andrea Hart ; Sony Agrawal ; John Pichardo ; Andrew Prongay ; Kuo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：January 22, 2009
• 年：2009
• 卷：52
• 期：2
• 页码：336-346
• 全文大小：299K
• 年卷期：v.52,no.2(January 22, 2009)
• ISSN：1520-4804

文摘

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-α and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P₁−P₃ macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P₃ imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.