RESUMO
A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARalpha/gamma agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
Assuntos
Hipoglicemiantes/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas/síntese química , Fatores de Transcrição/agonistas , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Hiperglicemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Camundongos , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia , Fatores de Transcrição/metabolismoRESUMO
A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual alpha/gamma agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.
Assuntos
Hipoglicemiantes/farmacologia , Oxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Administração Oral , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Oxazóis/química , Oxazóis/farmacocinética , Relação Estrutura-AtividadeRESUMO
A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.