Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Shi, Junxing²  Zhou, Longhu^1,3  Amblard, Franck^1,3  Bobeck, Drew R.²  Zhang, Hongwang^1,3  Liu, Peng^1,3  Bondada, Lavanya^1,3  McBrayer, Tamara R.²  Tharnish, Phillip M.²  Whitaker, Tony²  Coats, Steven J.²  Schinazi, Raymond F.^1,3 

[1] Emory Univ, Sch Med, Dept Pediat, Ctr AIDS Res, Atlanta, GA 30322 USA

[2] RFS Pharma LLC, Tucker, GA 30084 USA

[3] Vet Affairs Med Ctr, Decatur, GA 30033 USA

关键词: HCV;    NS5A inhibitor;    Antiviral;   

DOI  :  10.1016/j.bmcl.2012.03.089

来源: Elsevier

【 摘 要 】

NS5A inhibitors are a new class of direct-acting antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC50 value of 26 pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent. (C) 2012 Published by Elsevier Ltd.

【 授权许可】

Free