ASP4,000, a novel, selective, dipeptidyl peptidase 4 inhibitor with antihyperglycemic activity.

ASP4,000, (2S)-1-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecar bonitrile hydrochloride, is a novel dipeptidyl peptidase (DPP) 4 inhibitor. In the present study, we characterized the compound as an oral antidiabetic agent both in vitro and in vivo. ASP4,000 inhibited human recombinant DPP4 with an IC(50) value of 2.25 nM, and the enzyme-kinetic curve indicated that the inhibition type was competitive. In addition, ASP4,000 also potently inhibited DPP4 activity in human, rat, dog, and monkey plasma at concentrations of the order of 10(-9) M, and showed high selectivity against other related enzymes, including DPP8 and DPP9. The antihyperglycemic activity of ASP4,000 in vivo was examined using Zucker fa/fa rats, a type 2 diabetes animal model. A single oral administration of ASP4,000 at doses of 0.03-1 mg/kg suppressed plasma DPP4 activity, and then reduced the glucose level with increasing the active GLP-1 and insulin levels in oral glucose tolerance test. These results indicate that ASP4,000 is a potent, competitive, selective DPP4 inhibitor with antihyperglycemic activity, and could be a promising candidate agent for the treatment of patients with type 2 diabetes.