Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer's disease treatment
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
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-zdroje
- Klíčová slova
- 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-dehydrogenasy antagonisté a inhibitory metabolismus MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- benzothiazoly chemie farmakologie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- močovina analogy a deriváty chemie farmakologie MeSH
- molekulární struktura MeSH
- racionální návrh léčiv * MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 3-hydroxyacyl-CoA-dehydrogenasy MeSH
- benzothiazole MeSH Prohlížeč
- benzothiazoly MeSH
- HSD17B10 protein, human MeSH Prohlížeč
- inhibitory enzymů MeSH
- močovina 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.
Citace poskytuje 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
