2. Academic Validation
  3. 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

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

  • J Med Chem. 2023 Jul 13;66(13):8975-8992. doi: 10.1021/acs.jmedchem.3c00571.
Mohamed Salah 1 2,  Mariam Tahoun 1 3,  Jeannette Rudzitis-Auth 4,  Lisa Stotz 5,  Chris J van Koppen 6,  Matthias W Laschke 4,  Ahmed S Abdelsamie 7 8,  Martin Frotscher 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, 66123 Saarbrücken, Germany.
  • 2 Department of Pharmaceutical Chemistry, School of Pharmacy, Newgiza University (NGU), Newgiza, km 22 Cairo-Alexandria Desert Road, 12577 Cairo, Egypt.
  • 3 PharmaCenter Bonn, Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • 4 Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany.
  • 5 Department of Obstetrics & Gynecology, Saarland University Hospital, 66421 Homburg, Germany.
  • 6 ElexoPharm GmbH, Campus A12, 66123 Saarbrücken, Germany.
  • 7 Department of Chemistry of Natural and Microbial Products, Institute of Pharmaceutical and Drug Industries Research, National Research Centre, El-Buhouth St., Dokki, P.O. Box 12622 Cairo, Egypt.
  • 8 Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus E81, 66123 Saarbrücken, Germany.
PMID: 37369108 DOI: 10.1021/acs.jmedchem.3c00571
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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