RESUMEN
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores Enzimáticos/síntesis química , Fenetilaminas/síntesis química , Pirrolidinas/síntesis química , Animales , Glucemia/metabolismo , Ciclohexenos/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Inhibidores Enzimáticos/química , Femenino , Hipoglucemiantes/farmacología , Modelos Químicos , Conformación Molecular , Fenetilaminas/química , Pirrolidinas/química , RatasRESUMEN
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.