Activation of the GLP-1 receptor by chloropyrimidine derivatives

The anti-diabetic activities of a series of chloropyrimidine derviatives 2a-k and 4a-k were investigated after they were designed, synthesized, and docked against the GLP-1 receptor target. In comparison to exenatide, which was utilized as a reference drug, the three chloropyrimidine synthesized compounds 2c, 2f and 4c exhibited potent in vitro and in vivo antidiabetic activities. Interestingly, compounds 2c, 2f and 4c showed to be the most effective in lowering blood glucose levels and led to even higher glucose uptake than the reference drug, exenatide. Consistent with the in vitro and in vivo data, compounds 4c and 2f had the lowest docking energy scores (Glide-XP score = 5.1 kcal/mol) and the greatest ligand efficiency score (> − 0.40 kcal/mol) among all docked compounds. These findings give up new possibilities for the development of high-efficacy compounds to treat hyperglycemia.