title: The synthesis and evaluation of a novel class of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid hepatitis C virus polymerase NS5B inhibitors.
abstract: Herein we report the identification and evaluation of a novel series of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid derivatives identified from a deannulation study performed on the reported benzimidazole NS5B inhibitor, 1. This resulted in the identification of (E)-3-(2-(4-((4'-cyano-4-(4-hydroxypiperidine-1-carbonyl)biphenyl-2-yl)methoxy)phenyl)-1-cyclohexyl-1H-imidazol-4-yl)-2-methylacrylic acid (11) as a potent inhibitor of NS5B. Potential pathways for the further optimization of this series are suggested.
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway Wallingford, CT 06492, USA. scott.martin@bms.com
authors.forename: Scott W
authors.initials: SW
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: Glunz
authors.forename: Brett R
authors.initials: BR
authors.lastname: Beno
authors.forename: Carl
authors.initials: C
authors.lastname: Bergstrom
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Romine
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
authors.forename: Makenzie
authors.initials: M
authors.lastname: Newman
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Susan
authors.initials: S
authors.lastname: Roberts
authors.forename: Karen
authors.initials: K
authors.lastname: Rigat
authors.forename: Robert
authors.initials: R
authors.lastname: Fridell
authors.forename: Dike
authors.initials: D
authors.lastname: Qiu
authors.forename: Galina
authors.initials: G
authors.lastname: Knobloh
authors.forename: Ying-Kai
authors.initials: YK
authors.lastname: Wang
mesh_terms: D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008689:Methacrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D011789:Quantum Theory; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase
chemical_list: D008689:Methacrylates; D011720:Pyrazoles; D017361:Viral Nonstructural Proteins; C008384:methacrylic acid; C031280:pyrazole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase