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A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD 50 in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC 50 4.9 μM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes. Image 1 • Novel xanthine derivatives were designed through ring formation strategy. • Systematic optimization from previous hit 20i led to the new lead compound HBK001. • HBK001 had potent DPP-IV inhibition and moderate GPR119 agonism activity. • HBK001 hydrochloride with superior PK showed potent in vivo glucose-lowering effect. [ABSTRACT FROM AUTHOR]