RESUMO
A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
Assuntos
Azetidinas/química , Azetidinas/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Administração Oral , Animais , Azetidinas/síntese química , Disponibilidade Biológica , Cobre/farmacologia , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Diabetes Mellitus Experimental/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Glucose/metabolismo , Camundongos , Camundongos Mutantes , Estrutura Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Conformação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/sangueRESUMO
A novel series of 2-hydroxy-N-arylbenzenesulfonamides were identified to be ATP-citrate lyase (ACL) inhibitors with compound 9 displaying potent in vitro activity (IC(50)=0.13 microM). Chronic oral dosing of compound 9 in high-fat fed mice lowered plasma cholesterol, triglyceride, and glucose, as well as inhibited weight gain.