Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis

Bioorg Med Chem. 2017 Aug 15;25(16):4512-4525. doi: 10.1016/j.bmc.2017.06.050. Epub 2017 Jun 29.

Abstract

GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.

Keywords: Amino-pyrimidine derivatives; Angiogenesis; GPR4; Imidazo-pyridine derivatives; Inflammation; Pain.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arthritis / drug therapy
  • Arthritis / metabolism
  • COS Cells
  • Chlorocebus aethiops
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Mice
  • Molecular Structure
  • Pain / drug therapy
  • Pain / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • GPR4 protein, human
  • Receptors, G-Protein-Coupled