Discovery of Hepatitis C Virus NS3-4A Protease Inhibitors with Improved Barrier to Resistance and Favorable Liver Distribution

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• 作者：Beno卯t Moreau ; Jeff A. O鈥橫eara ; Jos茅e Bordeleau ; Michel Garneau ; Cedrickx Godbout ; Vida Gorys ; M茅lissa Leblanc ; Elisia Villemure ; Peter W. White ; Montse Llin脿s-Brunet
• 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：1770-1776
• 全文大小：314K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.