title: Benzimidazole Thumb Pocket I finger-loop inhibitors of HCV NS5B polymerase: improved drug-like properties through C-2 SAR in three sub-series.
abstract: SAR at the C-2 position of benzimidazole-based Thumb Pocket I inhibitors of HCV NS5B polymerase revealed parallel activity for distinct sub-series that harbor 5-hydroxytryptophan amides, neutral thiazole isosteres or recently disclosed cinnamic acid diamides. The consistent SAR among the three sub-series suggest a common binding mode to the Thumb Pocket I allosteric site. New inhibitors with sub-micromolar cell-based replicon potency and improved 'drug-like' features are disclosed along with preliminary characterization of their ADME-PK profile.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, Laval, Québec, Canada. pierre.beaulieu@boehringer-ingelheim.com
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dansereau
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: James
authors.initials: J
authors.lastname: Gillard
authors.forename: Ginette
authors.initials: G
authors.lastname: McKercher
authors.forename: Steven
authors.initials: S
authors.lastname: LaPlante
authors.forename: Lisette
authors.initials: L
authors.lastname: Lagacée
authors.forename: Louise
authors.initials: L
authors.lastname: Thauvette
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase