title: Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: from benzimidazole to indole scaffolds.
abstract: Benzimidazole-based allosteric inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified to a variety of topologically related scaffolds. Replacement of the polar benzimidazole core by lipophilic indoles led to inhibitors with improved potency in the cell-based subgenomic HCV replicon system. Transposing the indole scaffold into a previously described series of benzimidazole-tryptophan amides generated the most potent inhibitors of HCV RNA replication in cell culture reported to date in this series (EC(50) approximately 50 nM).
authors.affiliation: 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: James
authors.initials: J
authors.lastname: Gillard
authors.forename: Darren
authors.initials: D
authors.lastname: Bykowski
authors.forename: Christian
authors.initials: C
authors.lastname: Brochu
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dansereau
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Duceppe
authors.forename: Bruno
authors.initials: B
authors.lastname: Haché
authors.forename: Araz
authors.initials: A
authors.lastname: Jakalian
authors.forename: Lisette
authors.initials: L
authors.lastname: Lagacé
authors.forename: Steven
authors.initials: S
authors.lastname: LaPlante
authors.forename: Ginette
authors.initials: G
authors.lastname: McKercher
authors.forename: Elaine
authors.initials: E
authors.lastname: Moreau
authors.forename: Stéphane
authors.initials: S
authors.lastname: Perreault
authors.forename: Timothy
authors.initials: T
authors.lastname: Stammers
authors.forename: Louise
authors.initials: L
authors.lastname: Thauvette
authors.forename: Jeff
authors.initials: J
authors.lastname: Warrington
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
mesh_terms: D000494:Allosteric Regulation; D001562:Benzimidazoles / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D012093:Replicon / Q000187:drug effects*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D001562:Benzimidazoles; D007211:Indoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase