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
Inhibitors of the glucagon-like peptide-1 (GLP-1) degrading enzyme dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes in animal models and in human subjects. A novel series of cis-2,5-dicyanopyrrolidine alpha-amino amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. 1-({[1-(Hydroxymethyl)cyclopentyl]amino}acetyl)pyrrolidine-2,5-cis-dicarbonitrile (1c) is an achiral, slow-binding (time-dependent) inhibitor of DPP-IV that is selective for DPP-IV over other DPP isozymes and proline specific serine proteases, and which has oral bioavailability in preclinical species and in vivo efficacy in animal models. The mode of binding of the cis-2,5-dicyanopyrrolidine moiety was determined by X-ray crystallography. The hydrochloride salt of 1c was further profiled for development as a potential new treatment for type 2 diabetes.
Assuntos
Inibidores de Adenosina Desaminase , Adenosina Desaminase/química , Dipeptidil Peptidase 4/química , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/química , Hipoglicemiantes/síntese química , Nitrilas/síntese química , Pirrolidinas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Injeções Intravenosas , Masculino , Camundongos , Modelos Moleculares , Nitrilas/química , Nitrilas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of pyrrolidine based inhibitors of dipeptidyl peptidase IV were developed from a high throughput screening hit for the treatment of type 2 diabetes. Potency, selectivity, and pharmacokinetic properties were optimized resulting in the identification of a pre-clinical candidate for further profiling.