Discovery and pharmacological effects of a novel GPR142 antagonist

J Recept Signal Transduct Res. 2017 Jun;37(3):290-296. doi: 10.1080/10799893.2016.1247861. Epub 2016 Nov 3.

Abstract

GPR142 is a G-protein-coupled receptor (GPCR), whose most potent and efficacious ligand has been reported as being the natural amino acid l-tryptophan. GPR142 is highly expressed in pancreatic β-cells and immune cells, suggesting the receptor may play a role in the pathogenesis and development of diabetes or inflammatory diseases. In a previous report, we developed GPR142 agonists as insulin secretagogues. In this report, we show the discovery of a selective, potent small-molecule GPR142 antagonist, CLP-3094, and its pharmacological characteristics. These data support targeting this receptor for the treatment of chronic inflammatory diseases.

Keywords: GPR142 antagonist; KO mouse; anti-CII Ab-induced arthritis; inflammatory diseases; l-tryptophan.

MeSH terms

  • Benzimidazoles / chemistry*
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / metabolism
  • Drug Discovery
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Ligands
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / therapeutic use

Substances

  • Benzimidazoles
  • CLP-3094
  • GPR142 protein, human
  • Insulin
  • Ligands
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries