Lead Optimization of 17β-HSD1 Inhibitors of the (Hydroxyphenyl)naphthol Sulfonamide Type for the Treatment of Endometriosis

Claudia Henn; Henn C; Einspanier A; A. Einspanier; Almuth Einspanier; Sandrine Marchais‐Oberwinkler; Sandrine Marchais-Oberwinkler; Marchais-Oberwinkler S; Martin Frotscher; Frotscher M; Rolf W. Hartmann; Hartmann RW

doi:10.1021/jm201735j

Lead Optimization of 17β-HSD1 Inhibitors of the (Hydroxyphenyl)naphthol Sulfonamide Type for the Treatment of Endometriosis

Claudia Henn, Henn C, Einspanier A, A. Einspanier, Almuth Einspanier, Sandrine Marchais‐Oberwinkler, Sandrine Marchais-Oberwinkler, Marchais-Oberwinkler S, Martin Frotscher, Frotscher M, Rolf W. Hartmann, Hartmann RW

Journal of medicinal chemistry · 2012 · vol. 55(7) , pp. 3307–3318 · doi:10.1021/jm201735j · PMID:22380653 · W2313213549

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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

This study optimized (hydroxyphenyl)naphthol sulfonamides, yielding compound 30, a highly active and selective human 17β-HSD1 inhibitor with good intracellular activity, suitable for further ADMET studies and in vivo proof of concept.

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The paper reports lead optimization of (hydroxyphenyl)naphthol sulfonamide–type inhibitors targeting human 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1), presenting a large set of enzyme inhibition hit data and assay readouts. In vitro potency was measured using radiolabeled steroid substrates with [3H]E1 for human placenta cytosolic 17β-HSD1 and in T47D cells for 17β-HSD1, with IC50 values spanning from low nanomolar to higher nanomolar ranges; selectivity was also evaluated against 17β-HSD2 in placenta microsomes using [3H]E2. The data compilation is explicitly limited to reported affinity results, with no additional biological efficacy or mechanistic outcomes described in the provided text. This paper is centrally about endometriosis — it is titled and framed around developing 17β-HSD1 inhibitors for the treatment of endometriosis.

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Abstract

The reduction of estrone to estradiol, the most potent estrogen in human, is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). A promising approach for the treatment of estrogen-dependent diseases is the reduction of intracellular estradiol formation by inhibition of 17β-HSD1. For the species-specific optimization of the (hydroxyphenyl)naphthols, a combinatorial approach was applied and enhanced by a focused synthesis that resulted in the aromatic-substituted (hydroxyphenyl)naphthol sulfonamides. Rigidification of 12 led to the 4-indolylsulfonamide 30, which is a highly active and selective human 17β-HSD1 inhibitor, as well as a highly potent and selective inhibitor of 17β-HSD1 from Callithrix jacchus. It shows no affinity to the estrogen receptors α and β and good intracellular activity (T47D). Thus, compound 30 shows good properties for further ADMET studies and might be a candidate for the in vivo proof of concept in C. jacchus.

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Report error Found 69 Enz. 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data for this Ligand-Target Pair Affinity DataIC50: 19nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 25nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 28nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 29nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 30nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 31nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 32nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 32nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 33nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 35nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 46nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 49nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 53nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 74nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 92nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 157nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 188nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 196nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 213nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 223nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 238nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 240nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 246nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 316nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 352nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 367nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 371nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 374nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 391nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 396nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 396nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 402nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 403nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 408nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 429nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 439nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 440nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 446nMAssay Description:Inhibition of human placenta microsomal 17betaHSD2 using [3H]E2 as substrate after 20 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 462nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 462nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 498nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair Affinity DataIC50: 519nMAssay Description:Inhibition of human placenta cytosolic 17betaHSD1 using [3H]E1 as substrate after 10 mins by radioflow detection assayMore data for this Ligand-Target Pair Affinity DataIC50: 525nMAssay Description:Inhibition of 17betaHSD1 in human T47D cells using [3H]E1 as substrate incubated for 30 mins prior to substrate addition measured after 30 mins by ra...More data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Estradiol Dehydrogenases Naphthols Sulfonamides Animals Callithrix Cell Line, Tumor Endometriosis Estradiol Dehydrogenases Estrogen Receptor alpha Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptor beta Female Humans Naphthols Naphthols Naphthols Placenta Placenta

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[1] Endometriosis: Role of Ovarian Steroids in Initiation, Maintenance, and Suppression 1980

[2] Peritoneal endometriosis: validation of an in-vivo model 2001

[3] Induction of endometriosis in the marmoset monkey (Callithrix jacchus) 2006

[4] Novel Hydroxysteroid (17β) Dehydrogenase 1 Inhibitors Reverse Estrogen-Induced Endometrial Hyperplasia in Transgenic Mice 2010