Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer's disease treatment
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
Biotechnology and Biological Sciences Research Council - United Kingdom
PubMed
27287370
DOI
10.1016/j.bmcl.2016.05.087
PII: S0960-894X(16)30597-2
Knihovny.cz E-resources
- Keywords
- 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10), Alzheimer’s disease (AD), Amyloid binding alcohol dehydrogenase (ABAD), Amyloid-beta peptide (Aβ), Benzothiazole, Mitochondria, Riluzole,
- MeSH
- 3-Hydroxyacyl CoA Dehydrogenases antagonists & inhibitors metabolism MeSH
- Alzheimer Disease drug therapy MeSH
- Benzothiazoles chemistry pharmacology MeSH
- CHO Cells MeSH
- Cricetulus MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Urea analogs & derivatives chemistry pharmacology MeSH
- Molecular Structure MeSH
- Drug Design * MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3-Hydroxyacyl CoA Dehydrogenases MeSH
- benzothiazole MeSH Browser
- Benzothiazoles MeSH
- HSD17B10 protein, human MeSH Browser
- Enzyme Inhibitors MeSH
- Urea MeSH
Amyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.
References provided by Crossref.org
Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity
Novel Benzothiazole-based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer's Disease Treatment
