Discovery and characterization of a potent and selective EP4 receptor antagonist

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3176-8. doi: 10.1016/j.bmcl.2015.05.091. Epub 2015 Jun 4.

Abstract

EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.

Keywords: Amphoteric; Dog bioavailability; EP(4) antagonist; Prostaglandin pathway.

MeSH terms

  • Analgesics / chemistry*
  • Analgesics / metabolism
  • Analgesics / pharmacokinetics
  • Animals
  • Blood Cells / cytology
  • Blood Cells / drug effects
  • Blood Cells / metabolism
  • Dogs
  • Half-Life
  • Humans
  • Lipopolysaccharides / toxicity
  • Protein Binding
  • Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Analgesics
  • Lipopolysaccharides
  • Receptors, Prostaglandin E, EP4 Subtype
  • Tumor Necrosis Factor-alpha