Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives for GPR119 Agonistic Activity.

GPR119 is a promising target for the treatment of type 2 diabetes mellitus. Stimulating this receptor leads to the induction of glucose-dependent insulinotropic peptide and glucagon-like peptide 1, which improves systemic glucose homeostasis. Encouraged by our previous research, we replaced 5-nitropyrimidine with 1,3,5-triazine to reduce hepatotoxicity. A new series of compounds with a 1,3,5-triazine scaffold was synthesized and evaluated for their agonistic activities against human GPR119. Thirty-three compounds were synthesized and evaluated for their potential GPR119 agonist activities. Analogs with a 4-cyano and a 4-methylsulfonyl group in the aryl ring exhibited more potent activation than those analogs with a 4-trifluoromethyl group. Compound 3c had the most favorable EC50 value (hEC50 = 2.39 µM) and significantly induced glucagon-like peptide-1 secretion. Furthermore, docking simulations showed that compound 3c stably binds to the active site of GPR119.