Novel estrone mimetics with high 17beta-HSD1 inhibitory activity

Alexander Oster, Tobias Klein, Ruth Werth, Patricia Kruchten, Emmanuel Bey, Matthias Negri, Sandrine Marchais-Oberwinkler, Martin Frotscher, Rolf W Hartmann
Bioorganic & medicinal chemistry · 2010 · doi:10.1016/j.bmc.2010.03.065 · PMID:20413314
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Novel heterocyclic substituted biphenylols were designed to mimic estrone and inhibit 17beta-HSD1, with the most potent compound exhibiting nanomolar activity and low estrogen receptor affinity.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 · read from full text ⓘ

The paper reports bioactivity/affinity data for novel estrone mimetics, targeting human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) and type 2 (17β-HSD2), using binding/displacement assays with radiolabeled estrone or estradiol in placental enzyme preparations. For 17β-HSD1, multiple ligands show IC50 values in the sub-micromolar to low-micromolar range (e.g., 470 nM up to ~1.37 µM) based on displacement of [3H]estrone, indicating relatively high 17β-HSD1 inhibitory activity. For 17β-HSD2, IC50 values are also reported but appear substantially higher (hundreds of nM to several µM, with examples including ~850–7,110 nM and ~1.94–2.97 µM for different entries), suggesting weaker inhibition in this assay. The paper’s limitation, as provided here, is that it contains curated affinity assay results without additional experimental context such as synthesis details, selectivity profiling, or in vivo/functional outcomes. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match to estrogen/estrone metabolism targets relevant to endometriosis biology.

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Abstract

17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of estrone into estradiol, which is the most potent estrogen in humans. Lowering intracellular estradiol concentration by inhibition of this enzyme is a promising new option for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. Combination of ligand- and structure-based design resulted in heterocyclic substituted biphenylols and their aza-analogs as new 17beta-HSD1 inhibitors. The design was based on mimicking estrone, especially focusing on the imitation of the D-ring keto group with (substituted) heterocycles. Molecular docking provided insights into plausible protein-ligand interactions for this class of compounds. The most promising compound 12 showed an inhibitory activity in the high nanomolar range and very low affinity for the estrogen receptors alpha and beta. Thus, compound 12 is a novel tool for the elucidation of the pharmacological relevance of 17beta-HSD1 and might be a lead for the treatment of estrogen-dependent diseases.
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Report error Found 14 Enz. Inhib. hit(s) with all data for entry = 50031754 Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 470nMAssay Description:Displacement of [3H]estradiol from human placental 17beta-HSD2More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 560nMAssay Description:Displacement of [3H]estrone from human placental 17beta-HSD1More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 690nMAssay Description:Displacement of [3H]estrone from human placental 17beta-HSD1More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 850nMAssay Description:Displacement of [3H]estrone from human placental 17beta-HSD1More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 1.02E+3nMAssay Description:Displacement of [3H]estrone from human placental 17beta-HSD1More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 1.37E+3nMAssay Description:Displacement of [3H]estrone from human placental 17beta-HSD1More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 1.39E+3nMAssay Description:Displacement of [3H]estrone from human placental 17beta-HSD1More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 1.94E+3nMAssay Description:Displacement of [3H]estradiol from human placental 17beta-HSD2More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 2.37E+3nMAssay Description:Displacement of [3H]estradiol from human placental 17beta-HSD2More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 2.38E+3nMAssay Description:Displacement of [3H]estrone from human placental 17beta-HSD1More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 2.97E+3nMAssay Description:Displacement of [3H]estradiol from human placental 17beta-HSD2More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 3.64E+3nMAssay Description:Displacement of [3H]estradiol from human placental 17beta-HSD2More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 7.11E+3nMAssay Description:Displacement of [3H]estradiol from human placental 17beta-HSD2More data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Saarland University and Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 1.00E+4nMAssay Description:Displacement of [3H]estradiol from human placental 17beta-HSD2More data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

17-Hydroxysteroid Dehydrogenases Drug Design Estrone 17-Hydroxysteroid Dehydrogenases 17-Hydroxysteroid Dehydrogenases Antineoplastic Agents, Hormonal Antineoplastic Agents, Hormonal Biomimetics Biomimetics Breast Neoplasms Computer Simulation Estradiol Estradiol Estradiol Estrogen Receptor alpha Estrogen Receptor alpha Estrogens Estrogens Estrogens Estrone

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europepmc
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