Potent Dual Inhibitors of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 with a Suitable Pharmacokinetic Profile for In Vivo Proof-of-Principle Studies in an Endometriosis Mouse Model

Mohamed Salah, Mariam Tahoun, Jeannette Rudzitis-Auth, Jeannette Rudzitis‐Auth, L Stotz, Lisa Stotz, Chris J. van Koppen, Matthias W Laschke, Ahmed S. Abdelsamie, Martin Frotscher
Journal of medicinal chemistry · 2023 · vol. 66(13) , pp. 8975–8992 · doi:10.1021/acs.jmedchem.3c00571 · PMID:37369108 · W4382197506
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

Researchers designed and synthesized furan-based dual inhibitors of steroid sulfatase and 17β-hydroxysteroid dehydrogenase type 1, with compound 5 demonstrating potent enzyme inhibition and suitable pharmacokinetics for in vivo studies.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 · read from full text ⓘ

The paper reports discovery and characterization of potent dual inhibitors targeting steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), with inhibitory potency assessed in human placental cytosolic fractions and in T47D cells expressing the enzymes using radiolabeled substrates followed by HPLC measurement; it also evaluates an irreversible STS inhibition protocol via preincubation. Reported IC50 values for 17β-HSD1 and STS fall in the low nanomolar to hundreds of nanomolar range depending on assay format, while 17β-HSD2 inhibition is much weaker (micromolar-scale IC50 values). The study explicitly frames the work toward “in vivo proof-of-principle” in an endometriosis mouse model, but the provided text contains only affinity/potency data without the pharmacokinetic or in vivo efficacy results or stated limitations. This paper is centrally about endometriosis — it is positioned for in vivo proof-of-principle testing of dual STS/17β-HSD1 inhibition in an endometriosis mouse model.

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Abstract

Treating estrogen-dependent diseases like endometriosis with drugs suppressing local estrogen activation may be superior to existing endocrine therapies. Steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) are key enzymes of local estrogen activation. We describe the rational design, synthesis, and biological profilation of furan-based compounds as a novel class of dual STS/17β-HSD1 inhibitors (DSHIs). In T47D cells, compound 5 showed irreversible inhibition of STS and potent, reversible inhibition of 17β-HSD1. It was selective over 17β-HSD2 and displayed high metabolic stabilities in human and mouse liver S9 fractions. No effect on cell viability was detected up to 31 μM (HEK293) and 23 μM (HepG2), respectively, and there was no activation of the aryl hydrocarbon receptor (AhR) up to 3.16 μM. Single daily application to mice revealed steady-state plasma levels high enough to make this compound eligible for an in vivo proof-of-principle study in a mouse endometriosis model.
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Report error Found 43 Enz. 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5.60nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]E1 as substrate measured after 10 mins in presence of NADH by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 7.90nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 11nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate incubated for 1 hr followed by substrate addition measured after 24 ...More data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Irreversible inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate preincubated for 2 hr followed by substrate addition me...More data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]E1 as substrate measured after 10 mins in presence of NADH by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 36nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 38nMAssay Description:Inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate incubated for 1 hr followed by substrate addition measured after 24 ...More data for this Ligand-Target Pair Affinity DataIC50: 43nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]E1 as substrate measured after 10 mins in presence of NADH by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 53nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 58nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 68nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]E1 as substrate measured after 10 mins in presence of NADH by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 76nMAssay Description:Inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate incubated for 1 hr followed by substrate addition measured after 24 ...More data for this Ligand-Target Pair Affinity DataIC50: 79nMAssay Description:Irreversible inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate preincubated for 2 hr followed by substrate addition me...More data for this Ligand-Target Pair Affinity DataIC50: 80nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 83nMAssay Description:Inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate incubated for 1 hr followed by substrate addition measured after 24 ...More data for this Ligand-Target Pair Affinity DataIC50: 88nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 92nMAssay Description:Inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate incubated for 1 hr followed by substrate addition measured after 24 ...More data for this Ligand-Target Pair Affinity DataIC50: 110nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 140nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 140nMAssay Description:Inhibition of human 17beta-HSD1 expressed in human T47D cells using [3H]E1 as substrate incubated for 1 hr followed by substrate addition measured af...More data for this Ligand-Target Pair Affinity DataIC50: 150nMAssay Description:Inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate incubated for 1 hr followed by substrate addition measured after 24 ...More data for this Ligand-Target Pair Affinity DataIC50: 180nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]E1 as substrate measured after 10 mins in presence of NADH by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 400nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]E1 as substrate measured after 10 mins in presence of NADH by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 400nMAssay Description:Inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate incubated for 1 hr followed by substrate addition measured after 24 ...More data for this Ligand-Target Pair Affinity DataIC50: 420nMAssay Description:Irreversible inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate preincubated for 2 hr followed by substrate addition me...More data for this Ligand-Target Pair Affinity DataIC50: 430nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]E1 as substrate measured after 10 mins in presence of NADH by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 450nMAssay Description:Inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate incubated for 1 hr followed by substrate addition measured after 24 ...More data for this Ligand-Target Pair Affinity DataIC50: 460nMAssay Description:Irreversible inhibition of human STS expressed in human T47D cells using [3H]E1S as substrate preincubated for 2 hr followed by substrate addition me...More data for this Ligand-Target Pair Affinity DataIC50: 500nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]E1 as substrate measured after 10 mins in presence of NADH by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.40E+3nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 3.20E+3nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 3.20E+3nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 4.40E+3nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 6.20E+3nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 6.40E+3nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 7.50E+3nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair Affinity DataIC50: 7.70E+3nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]E2 as substrate measured after 20 mins in presence of NAD+ by HPLC analysisMore data for this Ligand-Target Pair

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mesh:D004715endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Steryl-Sulfatase

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