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Benzothiazolyl Ureas are Low Micromolar and Uncompetitive Inhibitors of 17β-HSD10 with Implications to Alzheimer's Disease Treatment
M. Schmidt, O. Benek, L. Vinklarova, M. Hrabinova, L. Zemanova, M. Chribek, V. Kralova, L. Hroch, R. Dolezal, A. Lycka, L. Prchal, D. Jun, L. Aitken, F. Gunn-Moore, K. Kuca, K. Musilek,
Language English Country Switzerland
Document type Journal Article
Grant support
NV19-09-00578
Ministerstvo Zdravotnictví Ceské Republiky
CZ.02.1.01/0.0/0.0/18_069/0010054
Ministerstvo Školství, Mládeže a Tělovýchovy
VT2019-2021
University of Hradec Kralove
SV2115-2018
University of Hradec Kralove
Postdoctoral job positions at UHK
University of Hradec Kralove
UHHK, 00179906
University Hospital Hradec Kralove
no. ED2.1.00/03.0078
NIMH NIH HHS - United States
204821/Z/16/Z
Wellcome Trust - United Kingdom
NLK
Free Medical Journals
from 2000
Freely Accessible Science Journals
from 2000
PubMed Central
from 2007
Europe PubMed Central
from 2007
ProQuest Central
from 2000-03-01
Open Access Digital Library
from 2000-01-01
Open Access Digital Library
from 2007-01-01
Health & Medicine (ProQuest)
from 2000-03-01
ROAD: Directory of Open Access Scholarly Resources
from 2000
PubMed
32192199
DOI
10.3390/ijms21062059
Knihovny.cz E-resources
- MeSH
- 3-Hydroxyacyl CoA Dehydrogenases antagonists & inhibitors chemistry MeSH
- Enzyme Activation MeSH
- Alzheimer Disease drug therapy MeSH
- Benzothiazoles chemistry MeSH
- Enzyme Inhibitors chemistry pharmacology MeSH
- Kinetics MeSH
- Humans MeSH
- Urea chemistry pharmacology MeSH
- Molecular Structure MeSH
- Recombinant Proteins MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson's disease, or Alzheimer's disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1-2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.
References provided by Crossref.org
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