7-Aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists

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• 作者：Puwen Zhang ; Jeffrey C. Kern ; Eugene A. Terefenko ; Andrew Fensome ; Ray Unwalla ; Zhiming Zhang ; Jeffrey Cohen ; Thomas J. Berrodin ; Matthew R. Yudt ; Richard C. Winneker ; Jay Wrobel
• 关键词：Progesterone receptor (PR) ; PR agonists ; PR antagonists ; Non-steroidal PR modulators
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：1 July 2008
• 年：2008
• 卷：16
• 期：13
• 页码：6589-6600
• 全文大小：450 K

文摘

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 (IC₅₀ 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.