RESUMO
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.
Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Cães , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
RESUMO
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.
Assuntos
Inibidores de Adenosina Desaminase , Amidas/síntese química , Glicoproteínas/antagonistas & inibidores , Pirrolidinas/síntese química , Inibidores de Serina Proteinase/síntese química , Amidas/farmacologia , Animais , Azetidinas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4 , Modelos Animais de Doenças , Flúor , Teste de Tolerância a Glucose , Concentração Inibidora 50 , Camundongos , Pirrolidinas/farmacologia , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
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.