Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC50 for a proof-of-principle study

Ahmed S. Abdelsamie, van Koppen CJ, Chris J. van Koppen, Bey E, Emmanuel Bey, Mohamed Salah, Carsten Börger, Börger C, Lorenz Siebenbürger, Siebenbürger L, Matthias W. Laschke, Michael D. Menger, Menger MD, Frotscher M, Martin Frotscher
European Journal of Medicinal Chemistry · 2017 · doi:10.1016/j.ejmech.2016.11.004 · PMID:27852458
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-08 ⓘ

This study synthesized and profiled (5-(3,5-dichloro-4-methoxyphenyl)thiophen-2-yl)(2,6-difluoro-3-hydroxyphenyl)methanone 20, a selective 17β-HSD1 inhibitor with sub-nanomolar IC50 and favorable properties for proof-of-principle studies.

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The paper reports the design, synthesis, and in vitro profiling of a selective 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) inhibitor, including a reported sub-nanomolar IC50 value, using human placental cytosolic 17β-HSD1 activity as measured by decreased conversion of [2,4,6,7-3H]-E1 to E2. In parallel profiling, the compound’s effect on human placental microsomal 17β-HSD2 is tested using [2,4,6,7-3H]-E2 as substrate with NAD+ and quantified by RP-HPLC, showing weaker inhibition across higher IC50 values for 17β-HSD2. The main limitation explicitly reflected in the provided text is that the results are described primarily at the biochemical enzyme-assay level without further in vivo validation or broader selectivity profiling details. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match related to estrogen-dependent disease targets and 17β-HSD inhibition.

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Abstract

Current endocrine therapeutics for the estrogen-dependent disease endometriosis often lead to considerable side-effects as they act by reducing estrogen action systemically. A more recent approach takes advantage of the fact that the weak estrogen estrone (E1) which is abundant in the plasma, is activated in the target cell to the highly estrogenic estradiol (E2) by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 17β-HSD1 is overexpressed in endometriosis and thus a promising target for the treatment of this disease, with the prospect of less target-associated side-effects. Potent inhibitors from the class of bicyclic substituted hydroxyphenylmethanones with sulfonamide moiety recently described by us suffered from high molecular weight and low selectivity over 17βHSD2, the physiological adversary of 17β-HSD1. We describe the structural optimizations leading to the discovery of (5-(3,5-dichloro-4-methoxyphenyl)thiophen-2-yl)(2,6-difluoro-3-hydroxyphenyl)methanone 20, which displayed a sub-nanomolar IC50 towards 17β-HSD1 as well as high selectivity over the type 2 enzyme, the estrogen receptors α and β and a range of hepatic CYP enzymes. The compound did neither show cellular toxicity, nor PXR activation nor mutagenicity in the AMES II assay. Additional favourable pharmacokinetic properties (rat) make 20 a suitable candidate for proof-of-principle studies using xenotransplanted immunodeficient rats.
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Report error Found 64 Enz. Inhib. hit(s) with all data for entry = 50048973 Affinity DataIC50: 0.200nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 0.300nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 0.400nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 0.5nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 0.5nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 0.900nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 1.20nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 1.30nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 1.40nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 1.40nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 2.10nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 2.10nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 2.40nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 3nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 3.30nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 3.5nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 4.70nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 6nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 6.5nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 7nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 7.20nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 7.20nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 8nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 9nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 9nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 11nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 11nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 11nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 19nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 21nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 26nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 26nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 29nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 29nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 35nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 38nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 39nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 39nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 41nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 47nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 47nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair Affinity DataIC50: 55nMAssay Description:Inhibition of human placental cytosolic 17beta-HSD1 assessed as reduction in activation of [2,4,6,7-3H]-E1 substrate to E2 after 10 mins in presence ...More data for this Ligand-Target Pair Affinity DataIC50: 55nMAssay Description:Inhibition of human placental microsomal 17beta-HSD2 using [2,4,6,7-3H]-E2 as substrate after 20 mins in presence of NAD+ by RP-HPLC methodMore data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

17-Hydroxysteroid Dehydrogenases Drug Design Enzyme Inhibitors Enzyme Inhibitors Estrogens 17-Hydroxysteroid Dehydrogenases 17-Hydroxysteroid Dehydrogenases Actins Actins Animals Chemistry Techniques, Synthetic Enzyme Inhibitors Enzyme Inhibitors Enzyme Inhibitors Estrogen Receptor alpha Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptor beta Estrogens Feasibility Studies

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