High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice

Meng Zhang; Yang Feng; Jia Wang; Jianwei Zhao; Ting Li; Min He; Dehua Yang; Olivier Nosjean; Jean Boutin; Pierre Renard; Ming-Wei Wang

doi:10.1371/journal.pone.0063861

High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice

PLoS One. 2013 May 21;8(5):e63861. doi: 10.1371/journal.pone.0063861. Print 2013.

Authors

Meng Zhang¹, Yang Feng, Jia Wang, Jianwei Zhao, Ting Li, Min He, Dehua Yang, Olivier Nosjean, Jean Boutin, Pierre Renard, Ming-Wei Wang

Affiliation

¹ The National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Abstract

G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simultaneously. Following screening of a small molecule compound library containing 312,000 synthetic and natural product-derived samples, one potent GPR119 agonist with novel chemical structure, MW1219, was identified. Exposure of MIN6 and GLUTag cells to MW1219 enhanced glucose-stimulated insulin secretion and GLP-1 release; once-daily oral dosing of MW1219 for 6 weeks in diabetic db/db mice reduced hemoglobin A1c (HbA1c) and improved plasma glucose, insulin and GLP-1 levels; it also increased glucose tolerance. The results demonstrate that MW1219 is capable of effectively controlling blood glucose level and may have the potential to be developed as a new class of anti-diabetic agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / pathology
Drug Evaluation, Preclinical
Glucagon-Like Peptide 1 / metabolism
HEK293 Cells
High-Throughput Screening Assays*
Humans
Hypoglycemic Agents / administration & dosage
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Hypoglycemic Agents / therapeutic use*
Insulin / metabolism
Insulin Secretion
Male
Mice
Mice, Inbred C57BL
Oxadiazoles / pharmacology
Oxadiazoles / therapeutic use
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / metabolism

Substances

AR 231453
GPR119 protein, human
Gpr119 protein, mouse
Hypoglycemic Agents
Insulin
Oxadiazoles
Pyrimidines
Receptors, G-Protein-Coupled
Glucagon-Like Peptide 1

Grants and funding

This work was supported in part by grants from the Ministry of Health of China (2012ZX09304011 and 2013ZX09507002), Shanghai Science and Technology Development Fund (11DZ2292200) and Les Laboratories Servier (France). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.