NVP DPP 728 dihydrochloride Description: Ki: Inhibit human DPP-IV amidolytic activity with a Ki of 11 nM Inhibitors of dipeptidyl peptidase 4, also known as DPP-4 inhibitors or gliptins, are a class of oral hypoglycemics that can be used to treat diabetes mellitus type 2. NVP DPP 728 dihydrochloride is a potent and orally active inhibitor of dipeptidyl peptidase (DPP)-IV. In vitro: NVP-DPP728 was found to inhibit human DPP-IV amidolytic activity with a Ki of 11 nM, a kon value of 1.3 x 105 M-1 s-1, and a koff of 1.3 x 10-3 s-1. NVP-DPP728 inhibited DPP-IV in a manner consistent with a two-step inhibition mechanism. Taken together, these data suggest that NVP-DPP728 inhibits DPP-IV through formation of a novel, reversible, nitrile-dependent complex with transition state characteristics . In vivo: Aging caused a decrease in early insulin response after an oral glucose challenge in aged Wistar or DPP-IV(+) F344 rats, but not in aged DPP-IV(-) F344 rats, compared with young control groups. Glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats was better than in aged DPP-IV(+) F344 and Wistar rats associated with the preservation of the early insulin response. NVP-DPP728 improved the glucose tolerance after an oral glucose challenge by potentiating the early insulin response throughout the inhibition of plasma DPP-IV activity in aged DPP-IV(+) Wistar andF34 4 rats. In contrast, NVP-DPP728 did not affect the glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats. These results indicate that treatment with NVP-DPP728 ameliorated glucose tolerance in aged rats by the direct inhibition of plasma DPP-IV activity and presumably the subsequent increase in endogenous incretin action . Clinical trial: NVP-DPP728 is currently in the preclinical development and no clinical trial is ongoing.