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

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 ratio...

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Published inJournal of medicinal chemistry Vol. 66; no. 13; pp. 8975 - 8992
Main Authors Salah, Mohamed, Tahoun, Mariam, Rudzitis-Auth, Jeannette, Stotz, Lisa, van Koppen, Chris J., Laschke, Matthias W., Abdelsamie, Ahmed S., Frotscher, Martin
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.07.2023
Amer Chemical Soc
Subjects
17-Hydroxysteroid Dehydrogenases
Animals
Chemistry, Medicinal
Endometriosis - drug therapy
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Estrogens - metabolism
Female
HEK293 Cells
Humans
Life Sciences & Biomedicine
Mice
Pharmacology & Pharmacy
Science & Technology
Steryl-Sulfatase
WOMEN
INDUCTION
ESTRONE
17-BETA-ESTRADIOL
ESTRADIOL
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Summary: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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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c00571