RESUMEN
New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the 'Western Portion' of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC50=380 nM rat mitochondria) with favorable PK properties (F=93%, t(1/2)=13.6h, dog).
Asunto(s)
Antioxidantes/farmacología , Antioxidantes/farmacocinética , Ácidos Grasos/metabolismo , Oxadiazoles/farmacología , Oxadiazoles/farmacocinética , Palmitoil Coenzima A/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Perros , Ácidos Grasos/química , Humanos , Conformación Molecular , Oxidación-Reducción/efectos de los fármacos , Palmitoil Coenzima A/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
We describe the synthesis of novel inhibitors of fatty acid oxidation as potential metabolic modulators for the treatment of stable angina. Replacement of the 2H-benzo[d]1,3-dioxolene ring system in our initial lead 3 with different benzthiazoles, benzoxazoles and introducing small alkyl substituents into the piperazine ring resulted in analogues with enhanced inhibitory activity against 1-(14)[C]-palmitoyl-CoA oxidation in isolated rat heart mitochondria (6, IC(50)=70 nM; 25, IC(50)=23 nM).
Asunto(s)
Compuestos Epoxi/farmacología , Ácidos Grasos/metabolismo , Animales , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Estructura Molecular , Oxidación-Reducción/efectos de los fármacos , Palmitoil Coenzima A/efectos de los fármacos , Palmitoil Coenzima A/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
New inhibitors of palmitoylCoA oxidation were synthesized based on a structurally novel lead, CVT-3501 (1). Investigation of structure-activity relationships was conducted with respect to potency of inhibition of cardiac mitochondrial palmitoylCoA oxidation and metabolic stability. Potent and metabolically stable analogues 33, 42, and 43 were evaluated in vitro for cytochrome P450 inhibition and potentially adverse electrophysiological effects. Compound 33 was also found to have favorable pharmacokinetic properties in rat.
