Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir
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- 作者：Makonen Belema ; Van N. Nguyen ; Carol Bachand ; Dan H. Deon ; Jason T. Goodrich ; Clint A. James ; Rico Lavoie ; Omar D. Lopez ; Alain Martel ; Jeffrey L. Romine ; Edward H. Ruediger ; Lawrence B. Snyder ; Denis R. St. Laurent ; Fukang Yang ; Juliang Zhu ; Henry S. Wong ; David R. Langley ; Stephen P. Adams ; Glenn H. Cantor ; Anjaneya Chimalakonda ; Aberra Fura ; Benjamin M. Johnson ; Jay O. Knipe ; Dawn D. Parker ; Kenneth S. Santone ; Robert A. Fridell ; Julie A. Lemm ; Donald R. O鈥橞oyle ; II ; Richard J. Colonno ; Min Gao ; Nicholas A. Meanwell ; Lawrence G. Hamann
- 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：2013-2032
- 全文大小：700K
- 年卷期：v.57,no.5(March 13, 2014)
- ISSN：1520-4804
文摘
The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1鈥?. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure鈥揳ctivity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38鈥?08% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.