RESUMEN
Weak peroxisome proliferator-activated receptor (PPAR) α agonists (fibrates) are used to treat dyslipidemia. This study compared the effects of the potent and selective PPARα agonist CP-778875 on peroxisomal ß-oxidation and cardiac and/or skeletal muscle injury with those of the weak PPARα agonist fenofibrate. We hypothesized that these muscle effects are mediated through the PPARα receptor, leading to increased ß-oxidation and consequent oxidative stress. CP-778875 (5 or 500 mg/kg) and fenofibrate (600 or 2,000â1,200 mg/kg, dose lowered because of intolerance) were administered to rats for six weeks. Standard end points, serum troponin I, heart and skeletal muscle ß-oxidation of palmitoyl-CoA, and acyl co-oxidase (AOX) mRNA were assessed. Both compounds dose-dependently increased the incidence and/or severity of cardiomyocyte degeneration and necrosis, heart weight, troponin I, and skeletal muscle degeneration. Mean heart ß-oxidation (3.4- to 5.1-fold control) and AOX mRNA (2.4- to 3.2-fold control) were increased with CP-778875 500 mg/kg and both doses of fenofibrate. ß-Oxidation of skeletal muscle was not affected by either compound; however, a significant increase in AOX mRNA (1.6- to 2.1-fold control) was observed with CP-778875 500 mg/kg and both doses of fenofibrate. Taken together, these findings were consistent with PPARα agonism and support the link between increased cardiac and skeletal muscle ß-oxidation and resultant muscle injury in the rat.
Asunto(s)
Fenofibrato/toxicidad , Corazón/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , PPAR alfa/agonistas , Animales , Análisis Químico de la Sangre , Peso Corporal , Relación Dosis-Respuesta a Droga , Femenino , Fenofibrato/farmacocinética , Hígado/química , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/metabolismo , Miocardio/química , Miocardio/metabolismo , Miocardio/patología , NAD/metabolismo , Peroxisomas/metabolismo , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad , Troponina I/sangre , Troponina I/metabolismoRESUMEN
SAR studies on the stereoisomers of CP-470,711 suggested that in vivo epimerization was taking place in rats. Further metabolism studies revealed that no epimerization was occurring in dogs, and that no epimerization was expected in humans. A mechanism for the in vivo epimerization is proposed involving an oxidation-reduction pathway of the secondary benzylic alcohol, in contrast to an acid/base-promoted epimerization of the same center during chemical synthesis.
Asunto(s)
Inhibidores Enzimáticos/metabolismo , L-Iditol 2-Deshidrogenasa/antagonistas & inhibidores , L-Iditol 2-Deshidrogenasa/metabolismo , Pirimidinas/metabolismo , Administración Oral , Animales , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hepatocitos/enzimología , Humanos , L-Iditol 2-Deshidrogenasa/sangre , L-Iditol 2-Deshidrogenasa/síntesis química , Oxidación-Reducción , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED(90) < or = 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED(90) values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day.