Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

Ahmed S Abdelsamie; Emmanuel Bey; Nina Hanke; Martin Empting; Rolf W Hartmann; Martin Frotscher

doi:10.1016/j.ejmech.2014.05.074

Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

Ahmed S Abdelsamie, Emmanuel Bey, Nina Hanke, Martin Empting, Rolf W Hartmann, Martin Frotscher

European journal of medicinal chemistry · 2014 · doi:10.1016/j.ejmech.2014.05.074 · PMID:24929290

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⚙ AI-generated summary by claude@2026-06, 2026-06-11 ⓘ

This study explored structure-activity relationships of bicyclic hydroxyphenylmethanones, discovering a novel potent inhibitor of human 17β-HSD1 with a thioether linker that also shows activity against the murine enzyme.

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This paper reports a structure–activity relationship study focused on bicyclic substituted hydroxyphenylmethanones as inhibitors of human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) and type 2 (17β-HSD2), using affinity measurements in human placental cytosolic (for HSD1) and microsomal (for HSD2) fractions. Inhibition was assayed by measuring decreased conversion of radiolabeled steroid substrates by HPLC after short incubation times, with reported IC50 values spanning a range (e.g., for HSD1, 22 nM to 836 nM; for HSD2, 51 nM to 752 nM). A major limitation explicitly evident from the provided text is that only assay hit/affinity data are shown, without broader pharmacological, selectivity, or mechanistic results. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Estradiol is the most potent estrogen in humans. It is known to be involved in the development and proliferation of estrogen dependent diseases such as breast cancer and endometriosis. The last step of its biosynthesis is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β- HSD1) which consequently is a promising target for the treatment of these diseases. Recently, we reported on bicyclic substituted hydroxyphenylmethanones as potent inhibitors of 17β-HSD1. The present study focuses on rational structural modifications in this compound class with the aim of gaining more insight into its structure-activity relationship (SAR). (4-Hydroxyphenyl)-(5-(3-hydroxyphenylsulfanyl)-thiophen-2-yl)methanone (25) was discovered as a member of a novel potent class of human 17β-HSD1 inhibitors. Computational methods were used to elucidate its interactions with the target protein. The compound showed activity also towards the murine 17β-HSD1 enzyme and thus is a starting point for the design of compounds suitable for evaluation in an animal disease model.

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Report error Found 19 Enz. Inhib. hit(s) with all data for entry = 50044628 Affinity DataIC50: 22nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 51nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 90nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 104nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 109nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 120nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 152nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 157nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 173nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 202nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 224nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 245nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 247nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 275nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 283nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 389nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 630nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 752nMAssay Description:Inhibition of human placental 17beta-HSD1 cytosolic fraction using [2, 4, 6, 7-3H]-estrone as substrate after 10 mins by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 836nMAssay Description:Inhibition of human placental 17beta-HSD2 microsomal fraction using [2, 4, 6, 7-3H]-estradiol as substrate after 20 mins by HPLC analysisMore data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

17-Hydroxysteroid Dehydrogenases Drug Discovery Enzyme Inhibitors Phenols Sulfides 17-Hydroxysteroid Dehydrogenases 17-Hydroxysteroid Dehydrogenases Animals Dose-Response Relationship, Drug Enzyme Inhibitors Enzyme Inhibitors Enzyme Inhibitors Humans Mice Models, Molecular Molecular Structure Phenols Phenols Phenols Structure-Activity Relationship

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