Author/Authors :
Adrian Hall، نويسنده , , Susan H. Brown، نويسنده , , Iain P. Chessell، نويسنده , , Anita Chowdhury، نويسنده , , Nicholas M. Clayton، نويسنده , , Tanya Coleman، نويسنده , , Gerard M.P. Giblin، نويسنده , , Beverley Hammond، نويسنده , , Mark P. Healy، نويسنده , , Matthew R. Johnson، نويسنده , , Ann Metcalf، نويسنده , , Anton D. Michel، نويسنده , , Alan Naylor، نويسنده , , Riccardo Novelli، نويسنده , , David J. Spalding، نويسنده , , Jennifer Sweeting، نويسنده ,
Abstract :
This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
Keywords :
EP1 antagonist , pyrrole , pain , Established FCA
