Discovery of {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetic acid (GSK726701A), a novel EP4 receptor partial agonist for the treatment of pain

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1892-1896. doi: 10.1016/j.bmcl.2018.03.091. Epub 2018 Mar 31.

Abstract

A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.

Keywords: Anti-hyperalgesic; Anti-inflammatory; Arthritis; EP4; EP4 receptor agonist; Neuropathic pain; PGE2; Pain; Prostaglandin E2 receptor 4.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / therapeutic use
  • Blood Cells / cytology
  • Blood Cells / drug effects
  • Blood Cells / metabolism
  • Dinoprostone / chemistry
  • Dinoprostone / therapeutic use
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Inhibitory Concentration 50
  • Isoindoles / chemistry*
  • Isoindoles / pharmacokinetics
  • Isoindoles / therapeutic use
  • Lipopolysaccharides / pharmacology
  • Pain / drug therapy
  • Pain / pathology
  • Pain / veterinary
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Rats
  • Receptors, Prostaglandin E, EP4 Subtype / agonists*
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • GSK726701A
  • Isoindoles
  • Lipopolysaccharides
  • Protein Isoforms
  • Receptors, Prostaglandin E, EP4 Subtype
  • Tumor Necrosis Factor-alpha
  • Dinoprostone