Design, synthesis, and antidiabetic activities of 5-methoxypyrimidine derivatives targeting GPR119 and DPP-4.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired insulin secretion. G protein-coupled receptor 119 (GPR119) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are promising therapeutic agents due to their complementary mechanisms in promoting insulin secretion and lowering blood glucose levels. In this study, we designed and synthesized a series of dual-target compounds by linking a 5-methoxypyrimidine-based GPR119 agonist to the DPP-4 inhibitors sitagliptin or vildagliptin via a flexible linker. Among them, compound 27 exhibited the strongest DPP-4 inhibitory activity with an inhibition rate of 97.5 % at 10 μM, along with potent GPR119 agonistic activity (EC50 = 1.3 μM). In an oral glucose tolerance test (oGTT) in mice, compound 27 demonstrated significant glucose-lowering effects. These findings suggest that dual GPR119/DPP-4 targeting may offer a promising strategy for T2DM treatment.