RESUMEN
A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipoglucemiantes/farmacología , Pirimidinas/farmacología , Pirrolidinas/farmacología , Administración Oral , Animales , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Perros , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Cyclohexylglycine amides of various fluorinated pyrrolidines and azetidines were prepared and tested for activity against dipeptidyl peptidase IV and in vivo in the KK mouse model of type 2 diabetes. The tetrafluoropyrrolidide, cis-3,4-difluoropyrrolidide and the fluorinated azetidides displayed unexpectedly strong activity.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Amidas/síntesis química , Glicoproteínas/antagonistas & inhibidores , Pirrolidinas/síntesis química , Inhibidores de Serina Proteinasa/síntesis química , Amidas/farmacología , Animales , Azetidinas , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4 , Modelos Animales de Enfermedad , Flúor , Prueba de Tolerancia a la Glucosa , Concentración 50 Inhibidora , Ratones , Pirrolidinas/farmacología , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
Diabetic dyslipidemia requires simultaneous treatment with hypoglycemic agents and lipid-modulating drugs. We recently described glycogen phosphorylase inhibitors that reduce glycogenolysis in cells and lower plasma glucose in ob/ob mice (J. Med. Chem., 41: 2934, 1998). In evaluating the series prototype, CP-320626, in dogs, up to 90% reduction in plasma cholesterol was noted after 2 week treatment. Cholesterol reductions were also noted in ob/ob mice and in rats. In HepG2 cells, CP-320626 acutely and dose-dependently inhibited cholesterolgenesis without affecting fatty acid synthesis. Inhibition occurred together with a dose-dependent increase in the cholesterol precursor, lanosterol, suggesting that cholesterolgenesis inhibition was due to lanosterol 14alpha-demethylase (CYP51) inhibition. In ob/ob mice, acute treatment with CP-320626 resulted in a decrease in hepatic cholesterolgenesis with concomitant lanosterol accumulation, further implicating CYP51 inhibition as the mechanism of cholesterol lowering in these animals. CP-320626 and analogs directly inhibited rhCYP51, and this inhibition was highly correlated with HepG2 cell cholesterolgenesis inhibition (R2 = 0.77). These observations indicate that CP-320626 inhibits cholesterolgenesis via direct inhibition of CYP51, and that this is the mechanism whereby CP-320626 lowers plasma cholesterol in experimental animals. Dual-action glycogenolysis and cholesterolgenesis inhibitors therefore have the potential to favorably affect both the hyperglycemia and the dyslipidemia of type 2 diabetes.
Asunto(s)
Amidas/farmacología , Anticolesterolemiantes/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/antagonistas & inhibidores , Hipoglucemiantes/farmacología , Indoles/farmacología , Oxidorreductasas/antagonistas & inhibidores , Amidas/sangre , Amidas/síntesis química , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/química , Colesterol/biosíntesis , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Indoles/sangre , Indoles/síntesis química , Lanosterol/sangre , Hígado/efectos de los fármacos , Hígado/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Oxidorreductasas/metabolismo , Ratas , Ratas Sprague-Dawley , Esterol 14-Desmetilasa , Relación Estructura-ActividadRESUMEN
1,5-Cyclooctadiene can be stereoselectively transformed into a substituted bicyclo[3.3.0]octane ring system under palladium catalysis with concomitant formation of three carbon-carbon bonds. Reaction with an aryl iodide or triflate and malonate gives an exo-endo product, while the reaction with a malonate in the presence of oxygen affords a bis-endo adduct.