title: Development ofN-(4-Phenoxyphenyl)benzenesulfonamide Derivatives as Novel Nonsteroidal Progesterone Receptor Antagonists.
abstract: We report here development ofN-(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 derivative20aas a lead compound for structural development. Among the synthesized compounds, 3-trifluoromethyl derivative32exhibited 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.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University , 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Chemistry, Faculty of Science, Ochanomizu University , 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kazui
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo , 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yoshioka
authors.affiliation: Department of Chemistry, Faculty of Science, Ochanomizu University , 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Tanatani
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University , 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Mori
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University , 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan; Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
keywords: N-(4-phenoxyphenyl)benzenesulfonamide; Progesterone; antagonist; nuclear receptor