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

• Type of Material: Article
• Authors: Junxing Shi, Emory University; Longhu Zhou, Emory University; Franck Amblard, Emory University; Drew R. Bobeck, RFS Pharma, LLC; HongWang Zhang, Emory University; Peng Liu, Emory University; Lavanya Bondada, Emory University; Tamara R. McBrayer, RFS Pharma, LLC; Phillip M. Tharnish, RFS Pharma, LLC; Tony Whitaker, RFS Pharma, LLC; Steven Coats, Emory University; Raymond Schinazi, Emory University
• Language: English
• Date: 2012-05-15
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2012
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2012.03.089
• Title of Journal or Parent Work: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• Volume: 22
• Issue: 10
• Start Page: 3488
• End Page: 3491
• Grant/Funding Information: R.F.S. is supported by CFAR NIH Grant 2P30-AI-050409 and by the Department of Veterans Affairs.
• Keywords: Chemistry, Medicinal; Science & Technology; Pharmacology & Pharmacy; NATURAL-HISTORY; HEPATITIS-C; Chemistry, Organic; Life Sciences & Biomedicine; Chemistry; Antiviral; Physical Sciences; IMPACT; HCV; NS5A inhibitor
• Research Categories: Health Sciences, Pharmacology; Chemistry, Organic; Health Sciences, Pharmacy

Abstract

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 EC 50 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. © 2012 Elsevier Ltd. All rights reserved.