title: Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors.
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.
authors.affiliation: RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA.
authors.forename: Junxing
authors.initials: J
authors.lastname: Shi
authors.forename: Longhu
authors.initials: L
authors.lastname: Zhou
authors.forename: Franck
authors.initials: F
authors.lastname: Amblard
authors.forename: Drew R
authors.initials: DR
authors.lastname: Bobeck
authors.forename: Hongwang
authors.initials: H
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Lavanya
authors.initials: L
authors.lastname: Bondada
authors.forename: Tamara R
authors.initials: TR
authors.lastname: McBrayer
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Tharnish
authors.forename: Tony
authors.initials: T
authors.lastname: Whitaker
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Coats
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase