Cyclic Sulfones as Novel P3-Caps for Hepatitis C Virus NS3/4A (HCV NS3/4A) Protease Inhibitors: Synthesis and Evaluation of Inhibitors with Improved Potency and Pharmacokinetic Profiles

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• 作者：Francisco Velzquez ; Mousumi Sannigrahi ; Frank Bennett ; Raymond G. Lovey ; Ashok Arasappan ; Stphane Bogen ; Latha Nair ; Srikanth Venkatraman ; Melissa Blackman ; Siska Hendrata ; Yuhua Huang ; Regina Huelgas
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 22, 2010
• 年：2010
• 卷：53
• 期：8
• 页码：3075-3085
• 全文大小：1000K
• 年卷期：v.53,no.8(April 22, 2010)
• ISSN：1520-4804

文摘

HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to combat the infection. The HCV NS3 protease inhibitor Boceprevir (1) was reported by our research group and efforts continue for the discovery of more potent compounds with improved pharmacokinetic profiles. A new series of HCV NS3 protease inhibitors having a cyclic sulfone P3-cap have been discovered. Compounds 43 and 44 showed K_i* values in the single-digit nM range and their cellular potency was improved by 10-fold compared to 1. The pharmacokinetic profiles of 43 and 44 in rats and monkeys were also improved to achieve higher plasma levels after oral administration.