title: Cyclic amide bioisosterism: strategic application to the design and synthesis of HCV NS5B polymerase inhibitors.
abstract: Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.
authors.affiliation: Medicinal Chemistry Department, Roche Palo Alto, LLC, Palo Alto, CA 94304, USA. Hanbiaoyang@gmail.com
authors.forename: Hanbiao
authors.initials: H
authors.lastname: Yang
authors.forename: Robert T
authors.initials: RT
authors.lastname: Hendricks
authors.forename: Nidhi
authors.initials: N
authors.lastname: Arora
authors.forename: Dov
authors.initials: D
authors.lastname: Nitzan
authors.forename: Calvin
authors.initials: C
authors.lastname: Yee
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Lucas
authors.forename: Yanli
authors.initials: Y
authors.lastname: Yang
authors.forename: Amy
authors.initials: A
authors.lastname: Fung
authors.forename: Sonal
authors.initials: S
authors.lastname: Rajyaguru
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Vincent J P
authors.initials: VJ
authors.lastname: Leveque
authors.forename: Julie Q
authors.initials: JQ
authors.lastname: Hang
authors.forename: Sophie Le
authors.initials: SL
authors.lastname: Pogam
authors.forename: Deborah
authors.initials: D
authors.lastname: Reuter
authors.forename: Gisele A
authors.initials: GA
authors.lastname: Tavares
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000577:Amides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase