Development of potential preclinical candidates with promising in vitro ADME profile for the inhibition of type 1 and type 2 17β-Hydroxysteroid dehydrogenases: Design, synthesis, and biological evaluation

Ahmed S Abdelsamie, Mohamed Salah, Lorenz Siebenbürger, Mostafa M Hamed, Carsten Börger, Chris J van Koppen, Martin Frotscher, Rolf W Hartmann
European journal of medicinal chemistry · 2019 · doi:10.1016/j.ejmech.2019.05.084 · PMID:31176098
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This study designed and synthesized novel inhibitors of 17β-HSD1 and 17β-HSD2 with improved in vitro ADME profiles, metabolic stability, and physicochemical properties, making them suitable for preclinical studies.

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The paper describes the design, synthesis, and biological evaluation of potential preclinical small-molecule candidates intended to inhibit human 17β-hydroxysteroid dehydrogenases type 1 (17β-HSD1) and type 2 (17β-HSD2). Enzyme inhibition was assessed using radioligand assays in human placental cytosolic or microsomal fractions—17β-HSD1 with [3H]-E1 and 17β-HSD2 with [3H]-E2—read out by radio-HPLC, yielding reported IC50 values across multiple enzyme–ligand pairs (with some mouse liver and homologous comparisons included for 17β-HSD2). The major stated caveat from the available text is that the excerpt provides largely assay/affinity data and does not detail in vivo efficacy or comprehensive characterization beyond these inhibition measurements. 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

Estrogens are the major female sex steroid hormones, estradiol (E2) being the most potent form in humans. Disturbing the balance between E2 and its weakly active oxidized form estrone (E1) leads to diverse types of estrogen-dependent diseases such as endometriosis or osteoporosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17β-HSD1 and 17β-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17β-HSD2 inhibitor in a bone fracture mouse model, using subcutaneous administration. In the present study, our aim was to improve the in vitro ADME profile of the most potent 17β-HSD1 and 17β-HSD2 inhibitors described so far. The optimized compounds show strong and selective inhibition of both the human enzymes and their murine orthologs. In addition, they display good metabolic stability in human liver microsomes (S9 fraction), low in vitro cytotoxicity as well as better aqueous solubility and physicochemical properties compared to the lead compounds. These achievements make the compounds eligible for testing in preclinical in vivo animal model studies on the effects of inhibition of 17β-HSD1 and 17β-HSD2.
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Report error Found 33 Enz. Inhib. hit(s) with all data for entry = 50008151 Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 0.400nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 0.5nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 0.5nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 0.900nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 1.10nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 1.30nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 1.5nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 2nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 3nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 6nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 6nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 6nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 7.30nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 8nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 9.5nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 15nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 15nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 18nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 18nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 18nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair TargetEstradiol 17-beta-dehydrogenase 2(Mouse) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 25nMAssay Description:Inhibition of mouse liver homogenate 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair TargetEstradiol 17-beta-dehydrogenase 2(Mouse) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 34nMAssay Description:Inhibition of mouse liver homogenate 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 35nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 41nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 44nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 59nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 75nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 76nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 80nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair TargetEstradiol 17-beta-dehydrogenase 2(Mouse) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 80nMAssay Description:Inhibition of mouse liver homogenate 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 159nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 2(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 239nMAssay Description:Inhibition of human placental microsomal fraction 17beta-HSD2 using [3H]-E2 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair Target17-beta-hydroxysteroid dehydrogenase type 1(Human) Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Helmholtz Institute For Pharmaceutical Research Saarland (Hips) Curated by ChEMBL Affinity DataIC50: 899nMAssay Description:Inhibition of human placental cytosolic fraction 17beta-HSD1 using [3H]-E1 as substrate in presence of NAD+ by radio-HPLC analysisMore data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

17-Hydroxysteroid Dehydrogenases Enzyme Inhibitors Estradiol Dehydrogenases Phenols Thiophenes 17-Hydroxysteroid Dehydrogenases Animals Binding Sites Drug Design Drug Stability Enzyme Inhibitors Enzyme Inhibitors Enzyme Inhibitors Enzyme Inhibitors Estradiol Dehydrogenases Estradiol Dehydrogenases Estradiol Dehydrogenases HEK293 Cells Humans Mice

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