Development of N-(4-Phenoxyphenyl)benzenesulfonamide Derivatives as Novel Nonsteroidal Progesterone Receptor Antagonists

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• 作者：Ayumi Yamada ; Yuko Kazui ; Hiromasa Yoshioka ; Aya Tanatani ; Shuichi Mori ; Hiroyuki Kagechika ; Shinya Fujii
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1028-1033
• 全文大小：372K
• ISSN：1948-5875

文摘

We report here development of N-(4-phenoxyphenyl)benzenesulfonamide derivatives as a novel class of nonsteroidal progesterone receptor (PR) antagonists. PR plays key roles in various physiological systems, including the female reproductive system, and PR antagonists are candidates for clinical treatment of multiple diseases, including uterine leiomyoma, endometriosis, breast cancer, and some psychiatric disorders. We found that the benzenesulfonanilide skeleton functions as a novel scaffold for PR antagonists, and we adopted 3-chlorobenzenesulfonyl derivative 20a as a lead compound for structural development. Among the synthesized compounds, 3-trifluoromethyl derivative 32 exhibited the most potent PR-antagonistic activity, with high binding affinity for PR and selectivity over androgen receptor (AR). It is structurally distinct from other nonsteroidal PR antagonists, including cyanopyrrole derivatives, and further modification is expected to afford novel selective PR modulators.