7-芳基-1,5-二氢-苯并[e][1,4]恶唑嗪-2-酮及其类似物作为非甾体类孕酮受体拮抗剂。
7-aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists.
作者信息
Zhang Puwen, Kern Jeffrey C, Terefenko Eugene A, Fensome Andrew, Unwalla Ray, Zhang Zhiming, Cohen Jeffrey, Berrodin Thomas J, Yudt Matthew R, Winneker Richard C, Wrobel Jay
机构信息
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
出版信息
Bioorg Med Chem. 2008 Jul 1;16(13):6589-600. doi: 10.1016/j.bmc.2008.05.018. Epub 2008 May 10.
Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones such as 10j and 10v demonstrated good in vitro potency (IC(50) of 10-30 nM) and selectivity (over 100-fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Several 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.
合成了新型7-芳基苯并[1,4]恶唑并[2,1-b]氮杂卓-2-酮，并将其作为非甾体孕酮受体（PR）调节剂进行评估。使用T47D细胞碱性磷酸酶测定法研究了7-芳基苯并[1,4]恶唑并[2,1-b]氮杂卓-2-酮的构效关系。一些7-芳基苯并[1,4]恶唑并[2,1-b]氮杂卓-2-酮，如10j和10v，在PR上显示出良好的体外效力（IC(50)为10-30 nM），并且对PR的选择性高于其他甾体受体，如糖皮质激素和雄激素受体（GR和AR）100倍以上。几种7-芳基苯并[1,4]恶唑并[2,1-b]氮杂卓-2-酮在大鼠子宫蜕膜化模型中具有活性。在该体内模型中，化合物10j和10u口服给药时在3 mg/kg剂量下具有活性。
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