Discovery of novel urea derivatives as dual-target hypoglycemic agents that activate glucokinase and PPARγ

•Novel urea derivatives as dual-acting agonists of GK and PPARγ were synthesized.•Several agonists exhibited high enzyme activity and moderate hypoglycemic efficacy.•The discovery may provide an effective approaching for treating T2DM.

Motivated by the discovery of a potential ligand that activates both glucokinase (GK) and perioxisome proliferator-activated receptor-γ (PPARγ), this work presents the rational design and synthesis of a series of novel urea derivatives as potent dual-target ligands of GK and PPARγ. The derivatives obtained, particularly compounds 14j, 14m, 15g, 15j, and 15s, showed relatively high enzyme activity and moderate blood glucose-lowering efficacy in normal ICR mice (GK activation fold >1.7, PPARγ activation percentage >38.8%, relative to rosiglitazone). The discovery of a dual-acting agent may provide an effective approach for treating type 2 diabetes mellitus.

Graphical abstractA novel series of urea derivatives as potent dual-acting agonists of GK and PPARγ were designed and synthesized. The binding model was predicted by molecular docking simulation.Figure optionsDownload full-size imageDownload as PowerPoint slide