title: Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype.
abstract: We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50<200nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors.
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. resgeneral.lav@boehringer-ingelheim.com
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.forename: Gulrez
authors.initials: G
authors.lastname: Fazal
authors.forename: Cédrickx
authors.initials: C
authors.lastname: Godbout
authors.forename: Oliver
authors.initials: O
authors.lastname: Hucke
authors.forename: Araz
authors.initials: A
authors.lastname: Jakalian
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Joly
authors.forename: Olivier
authors.initials: O
authors.lastname: Lepage
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
authors.forename: Julie
authors.initials: J
authors.lastname: Naud
authors.forename: Martin
authors.initials: M
authors.lastname: Poirier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux
authors.forename: Bounkham
authors.initials: B
authors.lastname: Thavonekham
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Stammers
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology* / Q000502:physiology; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D052999:Quinazolinones; D017361:Viral Nonstructural Proteins; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase