Design, Synthesis and Antidiabetic Activity of Novel Pyrrole-3-Carboximidamide Derivatives as Dipeptidyl Peptidase-4 Inhibitors

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired insulin secretion, and dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as an effective therapeutic option. A new series of pyrrole-3-carboximidamide derivatives was designed, synthesized, and evaluated as DPP-4 inhibitors. Most of the synthesized compounds exhibited favorable inhibitory activity against the DPP-4 enzyme, and compounds 5f and 5g were found to be the most potent inhibitors with IC₅₀ values of 12.19 and 23.08 nM, respectively. In vivo studies in diabetic Wistar rats showed that daily administration of compound 5g for 2 weeks resulted in a significant decrease in blood glucose compared with the control group. Moreover, compound 5g was effective in reducing plasma glucose in an acute oral glucose tolerance test in NMRI mice. The antiglycemic effects of compound 5g were comparable with standard treatment by sitagliptin, with no effect on normoglycemic rats. Both the in vitro and in vivo antidiabetic properties suggest that compound 5g could be considered a promising candidate for development as an antidiabetic medication.