RESUMO
2,4-Thiazolidinedione derivatives of 1,3-benzoxazinone were synthesized and evaluated for their PPAR-alpha and -gamma dual activation. DRF-2519, a compound obtained through SAR of TZD derivatives of benzoxazinone, has shown potent dual PPAR activation. In ob/ob mice, it showed better efficacy than the comparator molecules. In fat fed rat model, it showed significant improvement in lipid parameters, which was better than fibrates.
Assuntos
Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Animais , Hipoglicemiantes/química , Hipolipemiantes/química , Camundongos , Ratos , Ratos Sprague-Dawley , Tiazolidinedionas/químicaRESUMO
Coumarin derivatives of different heterocycles (5,7a-i, 10 and 11) were designed based on cyclisation of 2-ethoxy-3-phenylpropanoic acid and 2-benzylmalonic acid as novel lipid-lowering agents and their preliminary in vivo screening indicates 7c has moderate triglyceride-lowering activity.
Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Hipolipemiantes/síntese química , Hipolipemiantes/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Fenofibrato/farmacologia , Indicadores e Reagentes , Camundongos , Triglicerídeos/sangueRESUMO
A series of pyrimidinone derivatives of thiazolidinediones were synthesized. Their biological activity were evaluated in insulin resistant, hyperglycemic and obese db/db mice. In vitro PPARgamma transactivation assay was performed in HEK 293T cells. PMT13 showed the best biological activity in this series. PMT13 (5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione) showed better plasma glucose, triglyceride and insulin-lowering activity in db/db mice than rosiglitazone and pioglitazone. PMT13 showed better PPARgamma transactivation than the standard compounds. Pharmacokinetic study in Wistar rats showed good systemic exposure of PMT13. Twenty-eight day oral toxicity study in Wistar rats did not show any treatment-related adverse effects.