Diabetes 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.