Development of submicromolar 17β-HSD10 inhibitors and their in vitro and in vivo evaluation
Language English Country France Media print-electronic
Document type Journal Article
PubMed
37390508
DOI
10.1016/j.ejmech.2023.115593
PII: S0223-5234(23)00559-7
Knihovny.cz E-resources
- Keywords
- 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), Alzheimer's disease, Amyloid-binding alcohol dehydrogenase (ABAD), Enzyme inhibition, Pharmacokinetics,
- MeSH
- 17-Hydroxysteroid Dehydrogenases MeSH
- Alzheimer Disease * drug therapy MeSH
- Enzyme Inhibitors chemistry MeSH
- Humans MeSH
- Brain metabolism MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 17-Hydroxysteroid Dehydrogenases MeSH
- 3 (or 17)-beta-hydroxysteroid dehydrogenase MeSH Browser
- Enzyme Inhibitors MeSH
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).
References provided by Crossref.org
C-3 Steroidal Hemiesters as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 10
Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity
