RESUMEN

We report here the synthesis of a series of 5-[4-[2-[substituted phthalazinones-2(or 4)yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and 5-[4-[2-[2,3-benzoxazine-4-one-2-yl]ethoxy]phenylmethyl]thiazolidine-2,4-diones and their plasma glucose and plasma triglyceride lowering activity in db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. In vitro and in vivo pharmacological studies showed that the phthalazinone analogue has better activity. PHT46 (compound 5a), the best compound in this series, showed better in vitro PPARgamma transactivation potential than troglitazone and pioglitazone. In insulin resistant db/db mice, PHT46 showed better plasma glucose and triglyceride lowering activity than the standard drugs. Pharmacokinetic study in Wistar rats showed good systemic exposure of PHT46. Subchronic toxicity study in Wistar rats did not show any treatment-related adverse effect.

Asunto(s)

Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Hipolipemiantes/síntesis química , Hipolipemiantes/farmacología , Oxazinas/farmacología , Ftalazinas/farmacología , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Tiazolidinedionas , Factores de Transcripción/efectos de los fármacos , Triglicéridos/antagonistas & inhibidores , Animales , Línea Celular/efectos de los fármacos , Cromanos/farmacología , Modelos Animales de Enfermedad , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Oxazinas/química , Ftalazinas/química , Pioglitazona , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Triglicéridos/sangre , Troglitazona