title: Non-nucleoside benzimidazole-based allosteric inhibitors of the hepatitis C virus NS5B polymerase: inhibition of subgenomic hepatitis C virus RNA replicons in Huh-7 cells.
abstract: A previously disclosed series of non-nucleoside allosteric inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) was optimized to yield novel compounds with improved physicochemical properties and activity in cell-based assays. Replacement of ionizable carboxylic acids with neutral substituents in lead compounds produced inhibitors with cellular permeability and antiviral activity in a cell-based assay of subgenomic HCV RNA replication (replicon EC(50) as low as 1.7 microM). The improvement in potency in this ex vivo model of HCV RNA replication validates, in part, the mechanism by which this class of allosteric benzimidazole derivatives inhibits the polymerase and represents a significant step forward in the discovery of novel HCV therapeutics.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S2G5. pbeaulieu@lav.boehringer-ingelheim.com
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: Yves
authors.initials: Y
authors.lastname: Bousquet
authors.forename: Jean
authors.initials: J
authors.lastname: Gauthier
authors.forename: James
authors.initials: J
authors.lastname: Gillard
authors.forename: Martin
authors.initials: M
authors.lastname: Marquis
authors.forename: Ginette
authors.initials: G
authors.lastname: McKercher
authors.forename: Charles
authors.initials: C
authors.lastname: Pellerin
authors.forename: Serge
authors.initials: S
authors.lastname: Valois
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
mesh_terms: D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D012093:Replicon / Q000187:drug effects*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
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