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
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.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV , Flúor/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Animales , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/química , Perros , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , EstereoisomerismoRESUMEN
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.