Author/Authors :
Adrian Hall، نويسنده , , Stephen Atkinson، نويسنده , , Susan H. Brown، نويسنده , , Iain P. Chessell، نويسنده , , Anita Chowdhury، نويسنده , , Nicholas M. Clayton، نويسنده , , Tanya Coleman، نويسنده , , Gerard M.P. Giblin، نويسنده , , Robert J. Gleave، نويسنده , , Beverley Hammond، نويسنده , , Mark P. Healy، نويسنده , , Matthew R. Johnson، نويسنده , , Anton D. Michel، نويسنده , , Alan Naylor، نويسنده , , Riccardo Novelli، نويسنده , , David J. Spalding، نويسنده , , Sac P. Tang، نويسنده ,
Abstract :
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.
Keywords :
EP1 antagonist , pyrrole , isostere , pain , Established FCA
