RESUMEN
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.
Asunto(s)
Azetidinas/química , Azetidinas/farmacología , PPAR alfa/agonistas , PPAR gamma/agonistas , Administración Oral , Animales , Azetidinas/síntesis química , Disponibilidad Biológica , Cobre/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Diabetes Mellitus Experimental/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Glucosa/metabolismo , Ratones , Ratones Mutantes , Estructura Molecular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Conformación Proteica , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
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.