title: Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors.
abstract: A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a-c and 12a-c from a weak-binding fragment-like structure 1 as a starting point.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 rue Cunard, Laval, Québec, Canada H7S 2G5. 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: Jean
authors.initials: J
authors.lastname: Rancourt
authors.forename: Bounkham
authors.initials: B
authors.lastname: Thavonekham
authors.forename: Gulrez
authors.initials: G
authors.lastname: Fazal
authors.forename: Sylvie
authors.initials: S
authors.lastname: Goulet
authors.forename: Araz
authors.initials: A
authors.lastname: Jakalian
authors.forename: Dominic
authors.initials: D
authors.lastname: Wernic
authors.forename: Youla
authors.initials: Y
authors.lastname: Tsantrizos
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Poupart
authors.forename: Michael
authors.initials: M
authors.lastname: Bös
authors.forename: Ginette
authors.initials: G
authors.lastname: McKercher
authors.forename: Louise
authors.initials: L
authors.lastname: Thauvette
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; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D062105:Molecular Docking Simulation; D009705:Nucleosides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D017361:Viral Nonstructural Proteins; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase