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

Eur J Med Chem. 2016 Nov 29:124:103-116. doi: 10.1016/j.ejmech.2016.08.023.

Gang Li ¹, Yi Huan ¹, Baokun Yuan ¹, Jin Wang ¹, Qian Jiang ¹, Ziyun Lin ¹, Zhufang Shen ², Haihong Huang ³

Affiliations

1 State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
2 State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: shenzhf@imm.ac.cn.
3 State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: joyce@imm.ac.cn.

PMID: 27560285 DOI: 10.1016/j.ejmech.2016.08.023

Abstract

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.

Keywords

DPP-IV; Dual ligands; GPR119; Merged pharmacophores; Xanthine derivatives.

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