title: Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency.
abstract: Optimization of benzimidazole 5-carboxamide derivatives previously identified as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) has led to the discovery of potent analogues that inhibit the enzyme at low-nanomolar concentrations. Greater than 800-fold improvement in potency from the original lead structure was achieved through the combined effects of conformational rigidification, molecular size extension and the identification of previously unexploited interactions. Furthermore, these inhibitors retain specificity for HCV polymerase relative to other viral and mammalian RNA polymerases.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. pbeaulieu@lav.boehringer-ingelheim.com
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: Michael
authors.initials: M
authors.lastname: Bös
authors.forename: Yves
authors.initials: Y
authors.lastname: Bousquet
authors.forename: Patrick
authors.initials: P
authors.lastname: DeRoy
authors.forename: Gulrez
authors.initials: G
authors.lastname: Fazal
authors.forename: Jean
authors.initials: J
authors.lastname: Gauthier
authors.forename: James
authors.initials: J
authors.lastname: Gillard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Goulet
authors.forename: Ginette
authors.initials: G
authors.lastname: McKercher
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Poupart
authors.forename: Serge
authors.initials: S
authors.lastname: Valois
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D015394:Molecular Structure; D017955:Poliovirus / Q000201:enzymology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D000998:Antiviral Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases