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Piperazine oxadiazole inhibitors of acetyl-CoA carboxylase.
Bourbeau, Matthew P; Siegmund, Aaron; Allen, John G; Shu, Hong; Fotsch, Christopher; Bartberger, Michael D; Kim, Ki-Won; Komorowski, Renee; Graham, Melissa; Busby, James; Wang, Minghan; Meyer, James; Xu, Yang; Salyers, Kevin; Fielden, Mark; Véniant, Murielle M; Gu, Wei.
Afiliação
  • Bourbeau MP; 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.
J Med Chem ; 56(24): 10132-41, 2013 Dec 27.
Article em En | MEDLINE | ID: mdl-24294923
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxidiazóis / Acetil-CoA Carboxilase / Piperazinas / Inibidores Enzimáticos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxidiazóis / Acetil-CoA Carboxilase / Piperazinas / Inibidores Enzimáticos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article