Development of the first dual inhibitors for steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) : a novel treatment approach for endometriosis

• Main Author: Abdelrahim, Mohamed Salah Rezk
• Other Authors: Hartmann, Rolf W.
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: Saarländische Universitäts- und Landesbibliothek 2019
• Subjects: ddc:570; DML
• Online Access: http://nbn-resolving.org/urn:nbn:de:bsz:291--ds-282394; https://doi.org/10.22028/D291-28239

Endometriosis is an estrogen dependent disease (EDD) that has no satisfying treatment option, as the existing ones mainly comprise endocrine treatments that lead to severe systemic hypo-estrogenic side effects. Steroid sulfatase (STS) and 17β hydroxysteroid dehydrogenase type 1 (17β HSD1) are attractive new targets for the treatment of EDDs. Their inhibition leads to blockage of the local biosynthesis of estrogen without significantly affecting the circulating estrogen. The simultaneous inhibition of both enzymes appears to be more promising than the blockage of only one protein. The main aim of this study is the development of dual inhibitors of STS and 17β-HSD1 (DSHIs) that offers a novel treatment option for endometriosis without severe side effects. Using a designed multiple ligand (DML) approach, the first DSHIs were identified. Upon structural optimizations, highly potent inhibitors in cell-free and cellular assays were achieved that are characterized by high selectivity over 17β-HSD2 which plays a protective role in endometriosis. The DSHIs were able to efficiently reverse the E1-S and E1- induced T47D cell proliferation. The most interesting inhibitor described in this work is characterized by high metabolic stability in human and mouse hepatic S9 fraction, along with good physicochemical properties and high safety margins in cytotoxicity assays. Furthermore, this DSHI is considered a suitable candidate for in vivo proof of principle studies based on its pharmacokinetic profile. Endometriose ist eine Estrogen-abhängige Erkrankung für die bislang keine zufriedenstellende Therapieoption existiert. Zum Einsatz kommen hauptsächlich endokrine Behandlungen, die systemisch zu stark hypoestrogenen Zuständen und damit zusammenhängenden, ernsthaften Nebenwirkungen führen. Die Enzyme Steroid Sulfatase (STS) and 17β-Hydroxysteroid Dehydrogenase Typ 1 (17β-HSD1) sind attraktive, neuartige Targets zur Behandlung Estrogen-abhängiger Erkrankung. Ihre Inhibierung führt zur Hemmung lokaler Estrogen-Biosynthese, ohne ...