1,5-二芳基吡咯作为EP1受体拮抗剂的构效关系
Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists.
作者信息
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
机构信息
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
出版信息
Bioorg Med Chem Lett. 2006 Jul 15;16(14):3657-62. doi: 10.1016/j.bmcl.2006.04.073. Epub 2006 May 11.
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.
描述了一系列源自化合物1的新型1,5-联芳基吡咯EP1受体拮抗剂的初步构效关系。研究了用等排基团取代1的苄基。发现最有效的取代基是异丁基。环戊基甲基和环己基甲基也是有效的苄基取代基。环己基甲基衍生物19在该系列中表现出最低的代谢清除率。此外，还鉴定了几种高亲和力的取代苄基类似物。发现化合物39在大鼠中具有良好的生物利用度，并在已建立的弗氏完全佐剂炎性疼痛临床前模型中显示出疗效，计算得出的ED50为9.2mg/kg。
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