From virtual to clinical: The discovery of PGN-1531, a novel antagonist of the prostanoid EP4 receptor

Bioorg Med Chem Lett. 2014 May 1;24(9):2212-21. doi: 10.1016/j.bmcl.2014.02.068. Epub 2014 Mar 12.


In this Letter, we present the results of a hit-finding and lead optimization programme against the EP4 receptor (EP4R). In a short time period, we were able to discover five structurally diverse series of hit compounds using a combination of virtual screening methods. The most favoured hit, compound 6, was demonstrated to be a competitive antagonist of the EP4R. Compound 73 was identified following several rounds of optimization, which centred on improving both the primary EP4R affinity and selectivity against the related EP2R as well as the aqueous solubility. This work culminated in the preparation of PGN-1531, the sodium salt of 73, which showed a marked improvement in solubility (>10 mg/mL). PGN-1531 is a potent and selective antagonist at EP4Rs in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation.

Keywords: Cerebral vasodilatation; EP(4) receptor antagonist; Hit-finding; Lead optimization; Migraine.

MeSH terms

  • Brain / blood supply
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Ligands
  • Migraine Disorders / drug therapy
  • Models, Molecular
  • Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism
  • Vasodilation / drug effects


  • Ligands
  • Receptors, Prostaglandin E, EP4 Subtype