Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors

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• 作者：Makonen Belema ; Omar D. Lopez ; John A. Bender ; Jeffrey L. Romine ; Denis R. St. Laurent ; David R. Langley ; Julie A. Lemm ; Donald R. O鈥橞oyle ; II ; Jin-Hua Sun ; Chunfu Wang ; Robert A. Fridell ; Nicholas A. Meanwell
• 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：1643-1672
• 全文大小：1107K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs.