AbstractDiabetes mellitus is a chronic disease characteristic of poor glucose homeostasis that requires constant monitoring and adjustment of blood glucose levels by exogenous intervention. Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) are two incretin peptide hormones secreted from the intestine to synergize insulin's function at lowering blood glucose. The effects of GLP‐1 or GIP administration are short‐lived because they are rapidly inactivated by circulating dipeptidyl peptidase IV (DPP‐IV). Therefore, DPP‐IV inhibitors have been suggested to be a new class of molecule for treating hyperglycemic conditions in diabetic patients. The recent approval of Merck's Sitagliptin (a DPP‐IV‐specific inhibitor) indicates that DPP‐IV inhibition is a good target for new therapeutic agent development. The present study was conducted to evaluate the efficacies of a series of dipeptidyl derivatives with a sulfonamide moiety as DPP‐IV inhibitors. Among these compounds, D‐420720 was a potent inhibitor (Ki=39 nM), with a selectivity of 9160‐fold over the DPP‐II isozyme and elicits a hypoglycemic effect on oral glucose tolerance test with normal male ICR mice. Drug Dev Res 69: 514–525, 2008. © 2008 Wiley‐Liss, Inc.