title: From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons.
abstract: Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC(50)<100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK.
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: James
authors.initials: J
authors.lastname: Gillard
authors.forename: Eric
authors.initials: E
authors.lastname: Jolicoeur
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Poupart
mesh_terms: D000494:Allosteric Regulation; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000577:Amides; D001562:Benzimidazoles; D007211:Indoles; D017361:Viral Nonstructural Proteins; C514526:indole-5-carboxamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase