Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors

作者：Belema Makonen^*; Lopez Omar D; Bender John A; Romine Jeffrey L; St Laurent Denis R; Langley David R; Lemm Julie A; O'Boyle Donald R II; Sun Jin Hua; Wang Chunfu; Fridell Robert A; Meanwell Nicholas A

来源：Journal of Medicinal Chemistry, 2014, 57(5): 1643-1672.

DOI：10.1021/jm401793m

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.

• 出版日期2014-3-13