Design, Synthesis, and in Vitro Evaluation of Novel Aminomethyl-pyridines as DPP-4 Inhibitors.

A collection of novel aminomethyl-pyridines was designed, synthesized, and investigated as potential inhibitors of DPP-4. Optimization of the screening hit afforded a number of 5-aminomethyl-pyridines with inhibitory activity in the nanomolar range. Selected DPP-4 inhibitors were further evaluated for their selectivity over the closely related peptidase DPP-8. 5-Aminomethyl-4-(2,4-dichloro-phenyl)-6-methyl-pyridine-2-carboxylic acid cyanomethyl-amide showed high potency and excellent DPP-4 selectivity [IC50: 10 (DPP-4) and 6600 nM (DPP-8)] and no toxicity in mammalian cell culture.