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

Yamada A, Ayumi Yamada, Yuko Kazui, Kazui Y, H. YOSHIOKA, Hiromasa Yoshioka, Aya Tanatani, Mori S, Shuichi Mori, Hiroyuki Kagechika, Shinya Fujii
ACS medicinal chemistry letters · 2016 · vol. 7(12) , pp. 1028–1033 · doi:10.1021/acsmedchemlett.6b00184 · PMID:27994732 · PMC5151144 · W2519718130
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⚙ AI-generated summary by claude@2026-06, 2026-06-12 ⓘ

This study developed N-(4-phenoxyphenyl)benzenesulfonamide derivatives as novel nonsteroidal progesterone receptor antagonists, identifying a 3-trifluoromethyl derivative as a potent lead compound.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-12 · read from full text ⓘ

This paper reports the development of N-(4-phenoxyphenyl)benzenesulfonamide derivatives as nonsteroidal progesterone receptor (PR) antagonists, evaluating binding and functional antagonist activity using human T47D cell assays and biochemical displacement assays. The antagonism was tested by incubating T47D cells for 24 hours in the presence of progesterone and measuring PR-dependent activity by alkaline phosphatase assay, while binding/displacement was assessed using recombinant GST-tagged PR ligand-binding domain expressed in baculovirus-infected insect cells with radiolabeled progesterone. Reported IC50 values span from tens of nanomolar for the most potent compounds up to several micromolar for weaker derivatives, but the provided text does not include a stated comparison to controls, full chemical series details, or explicit limitations beyond an error in the record (“Report error”). Relevance to endometriosis: progesterone receptor antagonism is directly implicated because PR signaling is central to hormone-driven endometrial processes, though the paper text provided focuses on ligand optimization for PR antagonism rather than endometriosis or adenomyosis specifically.

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Abstract

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.
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Report error Found 56 Enz. 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Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 110nMAssay Description:Displacement of [1,2,6,7-3H]-PG from recombinant human GST-tagged PR-LBD (657 to 933 residues) expressed in baculovirus infected insect cells measure...More data for this Ligand-Target Pair Affinity DataIC50: 140nMAssay Description:Displacement of [1,2,6,7-3H]-PG from recombinant human GST-tagged PR-LBD (657 to 933 residues) expressed in baculovirus infected insect cells measure...More data for this Ligand-Target Pair Affinity DataIC50: 140nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 170nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 190nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 220nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 250nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 270nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 300nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 310nMAssay Description:Displacement of [1,2,6,7-3H]-PG from recombinant human GST-tagged PR-LBD (657 to 933 residues) expressed in baculovirus infected insect cells measure...More data for this Ligand-Target Pair Affinity DataIC50: 320nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 330nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 370nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 390nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 410nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 450nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 470nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 490nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 500nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 510nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 520nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 640nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 650nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 670nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 740nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 810nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 820nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 960nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 990nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 1.30E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 1.30E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 1.50E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 1.60E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 1.60E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 1.70E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 2.20E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 2.20E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 2.20E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 2.60E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 2.80E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 3.00E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 3.50E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 3.80E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair Affinity DataIC50: 5.00E+3nMAssay Description:Antagonist activity at progesterone receptor in human T47D cells incubated for 24 hrs in presence of P4 by alkaline phosphatase assayMore data for this Ligand-Target Pair

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endometriosis

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