title: Multi-parameter optimization of aza-follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 2: Impact of lipophilicity on promiscuity and in vivo toxicity.
abstract: We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients.
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: Dan
authors.initials: D
authors.lastname: Deon
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: Gulrez
authors.initials: G
authors.lastname: Fazal
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: Steven
authors.initials: S
authors.lastname: LaPlante
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* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000821:virology; 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; D000998:Antiviral Agents; D007211:Indoles; D008055:Lipids; D017361:Viral Nonstructural Proteins
keywords: HCV NS5B polymerase; Lipophilicity; Non-nucleoside inhibitor; Promiscuity; Thumb pocket 1