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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F23%3A10466920" target="_blank" >RIV/00179906:_____/23:10466920 - isvavai.cz</a>
Alternative codes found
RIV/60162694:G44__/24:00560281 RIV/62690094:18470/23:50020605
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=b3n._oKRKk" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=b3n._oKRKk</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2023.115593" target="_blank" >10.1016/j.ejmech.2023.115593</a>

Result language
angličtina
Original language name
Development of submicromolar 17 beta-HSD10 inhibitors and their in vitro and in vivo evaluation
Original language description
17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-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 physicochemical properties. This led to the identification of several submicromolar inhibitors (IC50 similar to 0.3 mu M), the most potent compounds within the benzothiazolylurea class known to date. The positive interaction with 17 beta-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).
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy

Project
<a href="/en/project/EF18_069%2F0010054" target="_blank" >EF18_069/0010054: IT4Neuro(degeneration)</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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