Structure–activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists

The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2 mg/kg.

Graphical abstractThe SAR of novel 1,5-biaryl pyrrole derivatives is described. Compound 43 displayed the highest affinity in an in vitro [3H]PGE2 binding assay, whilst 39 displayed activity in the established FCA model of inflammatory pain (ED50 = 9.2 mg/kg).Figure optionsDownload full-size imageDownload as PowerPoint slide