title: Piperazine oxadiazole inhibitors of acetyl-CoA carboxylase.
abstract: Acetyl-CoA carboxylase (ACC) is a target of interest for the treatment of metabolic syndrome. Starting from a biphenyloxadiazole screening hit, a series of piperazine oxadiazole ACC inhibitors was developed. Initial pharmacokinetic liabilities of the piperazine oxadiazoles were overcome by blocking predicted sites of metabolism, resulting in compounds with suitable properties for further in vivo studies. Compound 26 was shown to inhibit malonyl-CoA production in an in vivo pharmacodynamic assay and was advanced to a long-term efficacy study. Prolonged dosing with compound 26 resulted in impaired glucose tolerance in diet-induced obese (DIO) C57BL6 mice, an unexpected finding.
authors.affiliation: Therapeutic Discovery, ‡Metabolic Diseases Research, §Pharmacokinetics/Drug Metabolism, and ∥Comparative Biology & Safety Sciences, Amgen Inc. , 1 Amgen Center Dr, Thousand Oaks, California 91320, United States.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Bourbeau
authors.forename: Aaron
authors.initials: A
authors.lastname: Siegmund
authors.forename: John G
authors.initials: JG
authors.lastname: Allen
authors.forename: Hong
authors.initials: H
authors.lastname: Shu
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Ki-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Renee
authors.initials: R
authors.lastname: Komorowski
authors.forename: Melissa
authors.initials: M
authors.lastname: Graham
authors.forename: James
authors.initials: J
authors.lastname: Busby
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Meyer
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Kevin
authors.initials: K
authors.lastname: Salyers
authors.forename: Mark
authors.initials: M
authors.lastname: Fielden
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004032:Diet / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010879:Piperazines; D000103:Acetyl-CoA Carboxylase