title: Anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors with sub-micromolar potency in the cell-based replicon assay.
abstract: Optimization efforts on the anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors 1 and 2 resulted in the identification of multiple structural elements that contributed to improved cell culture potency. The additive effect of these elements resulted in compound 46, an inhibitor with enzymatic (IC50) and cell culture (EC50) potencies of less than 100 nanomolar.
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. Electronic address: timothy.stammers@boehringer-ingelheim.com.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Stammers
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.forename: Gulrez
authors.initials: G
authors.lastname: Fazal
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gagnon
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: Sylvie
authors.initials: S
authors.lastname: Goulet
authors.forename: Araz
authors.initials: A
authors.lastname: Jakalian
authors.forename: Steven
authors.initials: S
authors.lastname: LaPlante
authors.forename: Jean
authors.initials: J
authors.lastname: Rancourt
authors.forename: Bounkham
authors.initials: B
authors.lastname: Thavonekham
authors.forename: Dominik
authors.initials: D
authors.lastname: Wernic
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Direct-acting antiviral; HCV NS5B polymerase; Non-nucleoside inhibitor; Structure-based drug design; Thumb Pocket 2