Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

被引：41

作者：

Maynard, Andrew ^{[2
]}

Crosby, Renae M. ^{[1
]}

Ellis, Byron ^{[2
]}

Hamatake, Robert ^{[1
]}

Hong, Zhi ^{[1
]}

Johns, Brian A. ^{[1
]}

Kahler, Kirsten M. ^{[2
]}

Koble, Cecilia ^{[1
]}

Leivers, Anna ^{[1
]}

Leivers, Martin R. ^{[1
]}

Mathis, Amanda ^{[1
]}

Peat, Andrew J. ^{[1
]}

Pouliot, Jeffrey J. ^{[1
]}

Roberts, Christopher D. ^{[1
]}

Samano, Vicente ^{[1
]}

Schmidt, Rachel M. ^{[2
]}

Smith, Gary K. ^{[2
]}

Spaltenstein, Andrew ^{[1
]}

Stewart, Eugene L. ^{[2
]}

Thommes, Pia ^{[3
]}

Turner, Elizabeth M. ^{[1
]}

Voitenleitner, Christian ^{[1
]}

Walker, Jill T. ^{[1
]}

Waitt, Greg ^{[2
]}

Weatherhead, Jason ^{[1
]}

Weaver, Kurt ^{[2
]}

Williams, Shawn ^{[2
]}

Wright, Lois ^{[2
]}

Xiong, Zhiping Z. ^{[1
]}

Haigh, David ^{[3
]}

Shotwell, J. Brad ^{[1
]}

机构：

[1] GlaxoSmithKline, Infect Dis Med Discovery Unit, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline, Platform Technol & Sci, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline, Infect Dis Ctr Excellence Drug Discovery, Stevenage SG1 1NY, Herts, England

来源：

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

关键词：

HEPATITIS-C VIRUS; NONNUCLEOSIDE INHIBITORS; ANTIFUNGAL AGENT; RESISTANCE; MECHANISMS; NUCLEOTIDE; INITIATION; PROTEASE; SITE;

D O I：

10.1021/jm400317w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.

引用

页码：1902 / 1913

页数：12

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