In this Letter, we present the results of a hit-finding and lead optimization programme against the EP 4 receptor (EP 4 R). 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 EP 4 R. Compound 73 was identified following several rounds of optimization, which centred on improving both the primary EP 4 R affinity and selectivity against the related EP 2 R 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 (>10mg/mL). PGN-1531 is a potent and selective antagonist at EP 4 Rs in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation.