Bicyclic substituted hydroxyphenylmethanones as novel inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) for the treatment of estrogen-dependent diseases

Alexander Oster, Oster A, Stefan Hinsberger, Hinsberger S, Werth R, Ruth Werth, Marchais-Oberwinkler S, Sandrine Marchais-Oberwinkler, Frotscher M, Martin Frotscher, Rolf W Hartmann, Hartmann RW
Journal of medicinal chemistry · 2010 · doi:10.1021/jm101073q · PMID:20977238
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⚙ AI-generated summary by claude@2026-06, 2026-06-23 ⓘ

This study developed bicyclic substituted hydroxyphenylmethanones that potently and selectively inhibit 17β-HSD1 in vitro and in cell-based assays.

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

The study reports the identification and inhibitory potency of bicyclic substituted hydroxyphenylmethanones as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), with drug-like candidates tested against 17β-HSD1 and 17β-HSD2. Enzymatic inhibition was measured using radiolabeled substrates in human placenta assays, and several compounds were also evaluated for 17β-HSD1 inhibition in human T47D cells using [2,4,6,7-3H]-estrone, with reported IC50 values spanning from nanomolar to sub-micromolar ranges. A major caveat explicitly evident from the provided text is that only affinity/IC50 data are shown, with no additional mechanistic, selectivity, or in vivo efficacy information included here. Relevance to endometriosis: the paper focuses on estrogen-dependent disease targets via 17β-HSD1 inhibition, a pathway implicated in endometriosis via local estrogen biosynthesis, though the text provided does not explicitly mention endometriosis or adenomyosis.

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Abstract

Estradiol (E2), the most important estrogen in humans, is involved in the initiation and progression of estrogen-dependent diseases such as breast cancer and endometriosis. Its local production in the target cell is regulated by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes E2-formation by reduction of the weak estrogen estrone (E1). Because the enzyme is expressed in the diseased tissues, inhibition of 17β-HSD1 is considered as a promising therapy for the treatment of estrogen-dependent diseases. For the development of novel inhibitors, a structure- and ligand-based design strategy was applied, resulting in bicyclic substituted hydroxyphenylmethanones. In vitro testing revealed high inhibitory potencies toward human placental 17β-HSD1. Compounds were further evaluated with regard to selectivity (17β-HSD2, estrogen receptors ERα and ERβ), intracellular activity (T47D cells), and metabolic stability. The most promising compounds, 14 and 15, showed IC(50) values in the low nanomolar range in the cell-free and cellular assays (8-27 nM), more than 30-fold selectivity toward 17β-HSD2 and no affinity toward the ERs. The data obtained make these inhibitors interesting candidates for further preclinical evaluation.
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Report error Found 46 Enz. Inhib. hit(s) with all data for entry = 50032557 Affinity DataIC50: 5nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 6nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 8nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 17nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [2,4,6,7-3H]-estrone as substrate after 30 minsMore data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 19nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 19nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 21nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [2,4,6,7-3H]-estrone as substrate after 30 minsMore data for this Ligand-Target Pair Affinity DataIC50: 30nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [2,4,6,7-3H]-estrone as substrate after 30 minsMore data for this Ligand-Target Pair Affinity DataIC50: 30nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 33nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 35nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 49nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 57nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 69nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 86nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 95nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 95nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 107nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [2,4,6,7-3H]-estrone as substrate after 30 minsMore data for this Ligand-Target Pair Affinity DataIC50: 108nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 109nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 126nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [2,4,6,7-3H]-estrone as substrate after 30 minsMore data for this Ligand-Target Pair Affinity DataIC50: 199nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 207nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 240nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 246nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 367nMAssay Description:Inhibition of 17beta-HSD1 in human T47D cells using [2,4,6,7-3H]-estrone as substrate after 30 minsMore data for this Ligand-Target Pair Affinity DataIC50: 368nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 376nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 382nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 465nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 478nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 485nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 567nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 588nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 590nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 594nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 719nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 786nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 793nMAssay Description:Inhibition of human placenta 17beta-HSD2 using [2,4,6,7-3H]-17beta-estradiol as substrate after 10 minsMore data for this Ligand-Target Pair Affinity DataIC50: 945nMAssay Description:Inhibition of human placenta 17beta-HSD1 using [2,4,6,7-3H]-estrone as substrate after 10 minsMore data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Estradiol Dehydrogenases Phenols Thiazoles Thiophenes Cell Line, Tumor Drug Design Drug Stability Estradiol Dehydrogenases Estradiol Dehydrogenases Estrogen Receptor alpha Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptor beta Female Humans In Vitro Techniques Microsomes, Liver Microsomes, Liver Phenols Phenols

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