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

Gang Li; Yi Huan; Baokun Yuan; Jin Wang; Qian Jiang; Ziyun Lin; Zhufang Shen; Haihong Huang

doi:10.1016/j.ejmech.2016.08.023

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. Epub 2016 Aug 13.

Authors

Gang Li¹, Yi Huan¹, Baokun Yuan¹, Jin Wang¹, Qian Jiang¹, Ziyun Lin¹, Zhufang Shen², Haihong Huang³

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.

MeSH terms

Animals
Dipeptidyl Peptidase 4 / chemistry
Dipeptidyl Peptidase 4 / metabolism*
Dipeptidyl-Peptidase IV Inhibitors / chemistry
Dipeptidyl-Peptidase IV Inhibitors / metabolism
Dipeptidyl-Peptidase IV Inhibitors / pharmacology
Drug Discovery
Drug Stability
Humans
Hypoglycemic Agents / chemistry*
Hypoglycemic Agents / metabolism
Hypoglycemic Agents / pharmacology*
Mice
Molecular Docking Simulation
Protein Conformation
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship
Xanthine / chemistry*
Xanthine / metabolism
Xanthine / pharmacology*

Substances

Dipeptidyl-Peptidase IV Inhibitors
GPR119 protein, human
Hypoglycemic Agents
Receptors, G-Protein-Coupled
Xanthine
DPP4 protein, human
Dipeptidyl Peptidase 4