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Autor
Aitken, Laura 1 Andrys, Rudolf 1 Benek, Ondrej 1 Capek, Jan 1 Dolezal, Rafael 1 Fisar, Zdenek 1 Gunn-Moore, Frank 1 Handl, Jiri 1 Hatlapatkova, Jana 1 Hroch, Lukas 1 Hroudova, Jana 1 Karasova, Jana Zdarova 1 Kobrlova, Tereza 1 Medvecky, Matej 1 Miskerikova, Marketa 1 Musilek, Kamil 1 Rotterova, Aneta 1 Rousar, Tomas 1 Schmidt, Monika 1 Skarka, Adam 1
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Pracoviště
Charles University and General Univer... 1 University Hospital Hradec Kralove Bi... 1 University of Defence Faculty of Mili... 1 University of Hradec Kralove Faculty ... 1 University of Pardubice Faculty of Ch... 1 University of St Andrews School of Bi... 1 University of Warwick Bioinformatics ... 1
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Autor
Aitken, Laura 1 Andrys, Rudolf 1 Benek, Ondrej 1 Capek, Jan 1 Dolezal, Rafael 1 Fisar, Zdenek 1 Gunn-Moore, Frank 1 Handl, Jiri 1 Hatlapatkova, Jana 1 Hroch, Lukas 1 Hroudova, Jana 1 Karasova, Jana Zdarova 1 Kobrlova, Tereza 1 Medvecky, Matej 1 Miskerikova, Marketa 1 Musilek, Kamil 1 Rotterova, Aneta 1 Rousar, Tomas 1 Schmidt, Monika 1 Skarka, Adam 1
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Pracoviště
Charles University and General Univer... 1 University Hospital Hradec Kralove Bi... 1 University of Defence Faculty of Mili... 1 University of Hradec Kralove Faculty ... 1 University of Pardubice Faculty of Ch... 1 University of St Andrews School of Bi... 1 University of Warwick Bioinformatics ... 1
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Benek, Ondrej
Autor Benek, Ondrej 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: ondrej.benek@uhk.cz
- Vaskova, Michaela
- Miskerikova, Marketa
- Schmidt, Monika
- Andrys, Rudolf
- Rotterova, Aneta
- Skarka, Adam
- Hatlapatkova, Jana
- Karasova, Jana Zdarova
- Medvecky, Matej
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).
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