Discovery of novel xanthine compounds targeting DPP-IV and GPR119 as anti-diabetic agents

A series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 was discovered through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Systematic optimization of general structure 5 led to the identification of compound 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Compound 20i may serve as a tool compound for further design of anti-diabetic drugs targeting both DPP-IV and GPR119. A series of xanthine derivatives targeting DPP-IV and GPR119 was designed and synthesized through the pharmacophore merging strategy. Systematic optimization of general structure led to the identification of dual modulator 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. [Display omitted] •A series of xanthine derivatives targeting DPP-IV and GPR119 was synthesized.•Systematic optimization led to the identification of dual modulator 20i.•Compound 20i had a selective DPP-IV inhibition and good GPR119 agonism activity.•Compound 20i had a favorable metabolic stability.•Insulinotropic effect of compound 20i was glucose-concentration dependent.