title: Aza follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 1: Mitigating the genotoxic liability of an aniline metabolite.
abstract: A series of heterocyclic aza-analogs of BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce the liability associated with the release of a genotoxic aniline metabolite in vivo. Analog 4, containing a 2-aminopyridine aniline isostere that is negative in the Ames test was identified, and was found to provide comparable GT1a/1b potency to 2. Although the cross-species PK profile, poor predicted human liver distribution of analog 4 and allometry principles projected high doses to achieve a strong antiviral response in patients, this work has provided a path forward toward the design of novel thumb pocket 1 NS5B polymerase inhibitors with improved safety profiles.
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Bolger
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gagnon
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Stammers
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
mesh_terms: D000179:Acrylates / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000595474:(E)-3-(4-((1-((2-(5-chloro-pyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino)-cyclobutanecarbonyl)-amino)-2-ethoxy-phenyl)-acrylic acid; D000179:Acrylates; D000814:Aniline Compounds; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D017361:Viral Nonstructural Proteins; C023650:aniline
keywords: Ames; Antiviral; Genotoxicity; Hepatitis C virus; NS5B polymerase