Antihyperglycemic effects of ASP8497 in streptozotocin-nicotinamide induced diabetic rats: comparison with other dipeptidyl peptidase-IV inhibitors.

(2S,4S)-4-Fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate (ASP8497) is a novel dipeptidyl peptidase (DPP)-IV inhibitor. In this study, we investigated the antidiabetic potency, mechanism, and duration of action of ASP8497 both in vitro and in vivo, and compared it with the DPP-IV inhibitors vildagliptin, sitagliptin, and saxagliptin. ASP8497 inhibited rat plasma DPP-IV activity in vitro with an IC(50) value of 2.96 nmol/l, while those for vildagliptin, sitagliptin, and saxagliptin were 2.12, 8.98, and 2.00 nmol/l, respectively. In rats that had streptozotocin-nicotinamide-induced, mildly diabetes, oral administration of ASP8497 dose-dependently and sustainably inhibited plasma DPP-IV activity. In addition, ASP8497 dose-dependently and significantly improved glucose tolerance with a concomitant increase in plasma glucagon-like peptide 1 (GLP-1) and insulin levels at both 0.5 h and 8 h after dosing. The order of both potency and duration of action for plasma DPP-IV inhibition and glucose tolerance improvement was as follows: saxagliptin > ASP8497 = vildagliptin = sitagliptin. These results suggest that ASP8497 exerts a potent and long-acting DPP-IV inhibitory effect and improves glucose tolerance through glucose-dependent insulinotropic action via elevation of the GLP-1 level in streptozotocin-nicotinamide-induced mildly diabetic rats. This compound is expected to be useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes.