RESUMEN
Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido)butanoate (5, CBM-301940) exhibited excellent potency and in vivo PK/ADME properties. It is the most powerful stimulant of glucose oxidation reported to date in isolated working rat hearts. Compound 5 improved the cardiac efficiency and function in a rat heart global ischemia/reperfusion model, suggesting MCD inhibitors may be useful for the treatment of ischemic heart diseases.
Asunto(s)
Carboxiliasas/antagonistas & inhibidores , Cardiotónicos/síntesis química , Isoxazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Cardiotónicos/farmacocinética , Cardiotónicos/farmacología , Cristalografía por Rayos X , Isoxazoles/farmacocinética , Isoxazoles/farmacología , Conformación Molecular , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/fisiopatología , Reperfusión Miocárdica , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of heteroaryl-substituted bis-trifluoromethyl carbinols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Some thiazole-based derivatives showed potent in vitro MCD inhibitory activities and significantly increased glucose oxidation rates in isolated working rat hearts.