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  3. Development of submicromolar 17β-HSD10 inhibitors and their in vitro and in vivo evaluation

Development of submicromolar 17β-HSD10 inhibitors and their in vitro and in vivo evaluation

  • Eur J Med Chem. 2023 Oct 5;258:115593. doi: 10.1016/j.ejmech.2023.115593.
Ondrej Benek 1,  Michaela Vaskova 2,  Marketa Miskerikova 2,  Monika Schmidt 3,  Rudolf Andrys 2,  Aneta Rotterova 2,  Adam Skarka 2,  Jana Hatlapatkova 4,  Jana Zdarova Karasova 4,  Matej Medvecky 5,  Lukas Hroch 6,  Lucie Vinklarova 2,  Zdenek Fisar 7,  Jana Hroudova 7,  Jiri Handl 8,  Jan Capek 8,  Tomas Rousar 8,  Tereza Kobrlova 6,  Rafael Dolezal 6,  Ondrej Soukup 6,  Laura Aitken 9,  Frank Gunn-Moore 9,  Kamil Musilek 10
Affiliations

Affiliations

  • 1 University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: [email protected].
  • 2 University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.
  • 3 University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 4 University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 5 University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic; University of Warwick, Bioinformatics Research Technology Platform, Coventry, CV4 7AL, United Kingdom.
  • 6 University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 7 Charles University and General University Hospital in Prague, First Faculty of Medicine, Department of Psychiatry, Ke Karlovu 11, 120 00, Prague 2, Czech Republic.
  • 8 University of Pardubice, Faculty of Chemical Technology, Department of Biological and Biochemical Sciences, Studentska 573, Pardubice, 53210, Czech Republic.
  • 9 University of St. Andrews, School of Biology, Biomedical Science Research Complex, North Haugh, St. Andrews KY16 9ST, United Kingdom.
  • 10 University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: [email protected].
PMID: 37390508 DOI: 10.1016/j.ejmech.2023.115593
Abstract

17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a multifunctional mitochondrial Enzyme and putative drug target for the treatment of various pathologies including Alzheimer's disease or some types of hormone-dependent Cancer. In this study, a series of new benzothiazolylurea-based inhibitors were developed based on the structure-activity relationship (SAR) study of previously published compounds and predictions of their physico-chemical properties. This led to the identification of several submicromolar inhibitors (IC50 ∼0.3 μM), the most potent compounds within the benzothiazolylurea class known to date. The positive interaction with 17β-HSD10 was further confirmed by differential scanning fluorimetry and the best molecules were found to be cell penetrable. In addition, the best compounds weren't found to have additional effects for mitochondrial off-targets and cytotoxic or neurotoxic effects. The two most potent inhibitors 9 and 11 were selected for in vivo pharmacokinetic study after intravenous and peroral administration. Although the pharmacokinetic results were not fully conclusive, it seemed that compound 9 was bioavailable after peroral administration and could penetrate into the brain (brain-plasma ratio 0.56).

Keywords

17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10); Alzheimer's disease; Amyloid-binding alcohol dehydrogenase (ABAD); Enzyme inhibition; Pharmacokinetics.

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