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

Bioorg Med Chem Lett. 2012 May 15;22(10):3488-91. doi: 10.1016/j.bmcl.2012.03.089.

Junxing Shi ¹, Longhu Zhou, Franck Amblard, Drew R Bobeck, Hongwang Zhang, Peng Liu, Lavanya Bondada, Tamara R McBrayer, Phillip M Tharnish, Tony Whitaker, Steven J Coats, Raymond F Schinazi

Affiliations

Affiliation

1 RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA.

PMID: 22507961 DOI: 10.1016/j.bmcl.2012.03.089

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.

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