Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors

被引：59

作者：

Belema, Makonen ^{[1
]}

Lopez, Omar D. ^{[1
]}

Bender, John A. ^{[1
]}

Romine, Jeffrey L. ^{[1
]}

St Laurent, Denis R. ^{[1
]}

Langley, David R. ^{[3
]}

Lemm, Julie A. ^{[2
]}

O'Boyle, Donald R., II ^{[2
]}

Sun, Jin-Hua ^{[2
]}

Wang, Chunfu ^{[2
]}

Fridell, Robert A. ^{[2
]}

Meanwell, Nicholas A. ^{[1
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Dept Discovery Chem, Wallingford, CT 06492 USA

[2] Bristol Myers Squibb Res & Dev, Dept Virol Discovery, Wallingford, CT 06492 USA

[3] Bristol Myers Squibb Res & Dev, Dept Comp Assisted Drug Design, Wallingford, CT 06492 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 05期

关键词：

NONSTRUCTURAL PROTEIN 5A; DIRECT-ACTING ANTIVIRALS; HCV-GENOTYPE; DACLATASVIR PLUS SOFOSBUVIR; IN-VITRO ACTIVITY; RNA REPLICATION; CYCLOPHILIN INHIBITORS; TREATMENT-NAIVE; VIROLOGICAL RESPONSE; COMBINATION THERAPY;

D O I：

10.1021/jm401793m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1643 / 1672

页数：30

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