Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists |
| |
| Authors: | Hall Adrian Atkinson Stephen Brown Susan H Chessell Iain P Chowdhury Anita Clayton Nicholas M Coleman Tanya Giblin Gerard M P Gleave Robert J Hammond Beverley Healy Mark P Johnson Matthew R Michel Anton D Naylor Alan Novelli Riccardo Spalding David J Tang Sac P |
| |
| Affiliation: | Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. adrian.2.hall@gsk.com |
| |
| 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 9.2mg/kg. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ |
|
