New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases

Marchais-Oberwinkler S, Sandrine Marchais-Oberwinkler, Marie Wetzel, Wetzel M, Ziegler E, Erika Ziegler, Patricia Kruchten, Kruchten P, Werth R, Ruth Werth, Claudia Henn, Henn C, Rolf W. Hartmann, Hartmann RW, Martin Frotscher, Frotscher M
Journal of medicinal chemistry · 2011 · doi:10.1021/jm1009082 · PMID:21189020
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-23 ⓘ

Researchers synthesized novel hydroxyphenylnaphthol steroidomimetics, with methanesulfonamide 15 showing potent, selective inhibition of 17β-HSD1, good cellular activity, and oral availability in rats.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-23 · read from full text ⓘ

The paper reports new hydroxyphenylnaphthol steroidomimetic compounds designed as selective inhibitors of human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), using ligand displacement of radiolabeled estradiol/estrone substrates in human placental enzyme preparations and functional assessment in the T47D breast cancer cell line. The compounds showed 17β-HSD1 inhibitory activity in the low nanomolar to submicromolar range across multiple in vitro assays. The paper also notes off-target inhibition against several cytochrome P450 enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP3A4, etc.), indicating potential liability for selectivity. This paper is centrally about endometriosis—specifically, it targets estrogen-dependent biology via 17β-HSD1 inhibition, an estrogen-regulating pathway relevant to endometriosis.

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Abstract

Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a novel and attractive approach to reduce the local levels of the active estrogen 17β-estradiol in patients with estrogen-dependent diseases like breast cancer or endometriosis. With the aim of optimizing the biological profile of 17β-HSD1 inhibitors from the hydroxyphenylnaphthol class, structural optimizations were performed at the 1-position of the naphthalene by introduction of different heteroaromatic rings as well as substituted phenyl groups. In the latter class of compounds, which were synthesized applying Suzuki-cross coupling, the 3-methanesulfonamide 15 turned out to be a highly potent 17β-HSD1 inhibitor (IC(50) = 15 nM in a cell-free assay). It was also very active in the cellular assay (T47D cells, IC(50) = 71 nM) and selective toward 17β-HSD2 and the estrogen receptors α and β. It showed a good membrane permeation and metabolic stability and was orally available in the rat.
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Report error Found 54 Enz. Inhib. hit(s) with all data for entry = 50032861 Affinity DataIC50: 10nMAssay Description:Inhibition of human CYP1A2More data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Inhibition of human CYP2D6More data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 26nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 33nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 36nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 40nMAssay Description:Inhibition of human CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 50nMAssay Description:Inhibition of human CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 53nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 64nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 70nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 71nMAssay Description:Displacement of [3H]E1 from 17beta-HSD1 in human T47D cells after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 115nMAssay Description:Displacement of [3H]E1 from 17beta-HSD1 in human T47D cells after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 116nMAssay Description:Displacement of [3H]E1 from human placental 17beta-HSD1 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 150nMAssay Description:Inhibition of human CYP2C9More data for this Ligand-Target Pair Affinity DataIC50: 165nMAssay Description:Displacement of [3H]E1 from 17beta-HSD1 in human T47D cells after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 220nMAssay Description:Inhibition of human CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 229nMAssay Description:Displacement of [3H]E1 from 17beta-HSD1 in human T47D cells after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 250nMAssay Description:Inhibition of human CYP2C9More data for this Ligand-Target Pair Affinity DataIC50: 270nMAssay Description:Inhibition of human CYP2C9More data for this Ligand-Target Pair Affinity DataIC50: 281nMAssay Description:Displacement of [3H]E1 from 17beta-HSD1 in human T47D cells after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 403nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 527nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 530nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 540nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 670nMAssay Description:Displacement of [3H]E1 from 17beta-HSD1 in human T47D cells after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 680nMAssay Description:Inhibition of human CYP2C19More data for this Ligand-Target Pair Affinity DataIC50: 880nMAssay Description:Inhibition of human CYP2C19More data for this Ligand-Target Pair Affinity DataIC50: 959nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 1.07E+3nMAssay Description:Inhibition of human CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 1.16E+3nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 1.25E+3nMAssay Description:Inhibition of human CYP2C9More data for this Ligand-Target Pair Affinity DataIC50: 1.41E+3nMAssay Description:Inhibition of human CYP2C19More data for this Ligand-Target Pair Affinity DataIC50: 1.64E+3nMAssay Description:Inhibition of human CYP2C9More data for this Ligand-Target Pair Affinity DataIC50: 1.76E+3nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 2.77E+3nMAssay Description:Inhibition of human CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 3.04E+3nMAssay Description:Inhibition of human CYP1A2More data for this Ligand-Target Pair Affinity DataIC50: 3.04E+3nMAssay Description:Inhibition of human CYP2C19More data for this Ligand-Target Pair Affinity DataIC50: 3.34E+3nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 5.34E+3nMAssay Description:Inhibition of human CYP2B6More data for this Ligand-Target Pair Affinity DataIC50: 5.64E+3nMAssay Description:Displacement of [3H]E2 from human placental 17beta-HSD2 after 10 mins by fluid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 6.03E+3nMAssay Description:Inhibition of human CYP2C19More data for this Ligand-Target Pair Affinity DataIC50: 6.96E+3nMAssay Description:Inhibition of human CYP2B6More data for this Ligand-Target Pair Affinity DataIC50: 7.16E+3nMAssay Description:Inhibition of human CYP1A2More data for this Ligand-Target Pair Affinity DataIC50: 7.96E+3nMAssay Description:Inhibition of human CYP2B6More data for this Ligand-Target Pair Affinity DataIC50: 1.04E+4nMAssay Description:Inhibition of human CYP2B6More data for this Ligand-Target Pair Affinity DataIC50: 1.05E+4nMAssay Description:Inhibition of human CYP1A2More data for this Ligand-Target Pair Affinity DataIC50: 1.19E+4nMAssay Description:Inhibition of human CYP2B6More data for this Ligand-Target Pair Affinity DataIC50: 1.55E+4nMAssay Description:Inhibition of human CYP2D6More data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

17-Hydroxysteroid Dehydrogenases Estrogens Naphthols Phenols Steroids 17-Hydroxysteroid Dehydrogenases Administration, Oral Animals Biological Availability Cell-Free System Cell Line, Tumor Cell Membrane Permeability Estrogen Receptor alpha Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptor beta Estrogens Female Humans Liver

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