title: Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery and preliminary SAR of benzimidazole derivatives.
abstract: Benzimidazole 5-carboxamide derivatives from a combinatorial screening library were discovered as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV). Initial hit-to-lead activities taking advantage of high-throughput parallel synthetic techniques, identified a 1,2-disubstituted benzimidazole 5-carboxylic acid scaffold as the minimum core for biological activity. Potent analogues in this series inhibit the polymerase at low micromolar concentrations and provide an attractive "drug-like" lead structure for further optimization and the development of potential HCV therapeutics.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, H7S 2G5, Laval (Québec), Canada. 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: 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: Steven
authors.initials: S
authors.lastname: LaPlante
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Poupart
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Ginette
authors.initials: G
authors.lastname: McKercher
authors.forename: Charles
authors.initials: C
authors.lastname: Pellerin
authors.forename: Volkhard
authors.initials: V
authors.lastname: Austel
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase