1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure–activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives

Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP1 receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP1 receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.

Graphical abstractSubstitution of the benzoic acid moiety of compounds such as 1a led to the identification of 1h, which was active in the established FCA model of inflammatory pain and showed good pharmacokinetics in the rat.Figure optionsDownload full-size imageDownload as PowerPoint slide