McKeown Stephen C, Hall Adrian, Giblin Gerard M P, Lorthioir Olivier, Blunt Richard, Lewell Xiao Q, Wilson Richard J, Brown Susan H, Chowdhury Anita, Coleman Tanya, Watson Stephen P, Chessell Iain P, Pipe Adrian, Clayton Nick, Goldsmith Paul
Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Bioorg Med Chem Lett. 2006 Sep 15;16(18):4767-71. doi: 10.1016/j.bmcl.2006.06.086. Epub 2006 Jul 14.
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.
描述了一系列新型EP1受体拮抗剂的发现、合成及构效关系（SAR）。从化学文库中鉴定出的吡唑酸4具有理想的理化性质、出色的体外微粒体抑制和细胞色素P450（CYP450）特征以及良好的血液暴露水平。该化合物在大鼠疼痛模型中的半数有效剂量（ED50）为1.3mg/kg。利用高效的文库化学方法在体外试验中鉴定出了一系列活性更强的类似物。这些EP1拮抗剂有潜力作为治疗PGE2介导疼痛的药物。
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