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1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders

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Date
2018
Author
Benek, Ondrej
Hroch, Lukas
Aitken, Laura
Gunn-Moore, Frank
Vinklarova, Lucie
Kuca, Kamil
Perez, Daniel I.
Perez, Concepcion
Martinez, Ana
Fisar, Zdenek
Musilek, Kamil
Keywords
Alzheimer's disease
Amyloid-beta binding alcohol dehydrogenase (ABAD)
Benzothiazole
Casein kinase 1 (CK1)
Neurodegeneration
RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
QD Chemistry
QH301 Biology
NDAS
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Abstract
Several neurodegenerative disorders including Alzheimer’s disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease’s progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.
Citation
Benek , O , Hroch , L , Aitken , L , Gunn-Moore , F , Vinklarova , L , Kuca , K , Perez , D I , Perez , C , Martinez , A , Fisar , Z & Musilek , K 2018 , ' 1-(Benzo[ d ]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders ' , Journal of Enzyme Inhibition and Medicinal Chemistry , vol. 33 , no. 1 , pp. 665-670 . https://doi.org/10.1080/14756366.2018.1445736
Publication
Journal of Enzyme Inhibition and Medicinal Chemistry
Status
Peer reviewed
DOI
https://doi.org/10.1080/14756366.2018.1445736
ISSN
1475-6374
Type
Journal article
Rights
© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Description
This work was supported by the Ministry of Health of the Czech Republic [no. NV15-28967 A], Specific Research Project of Faculty of Science, University of Hradec Kralove [no. 2103-2017], National Institute of Mental Health [NIMH CZ; no. ED2.1.00/03.0078] from the European Regional Development Fund, COST CA15135, The Alzheimer’s Society (specifically The Barcopel Foundation), The Rosetrees trust and The Biotechnology and Biological Sciences Research Council (BBSRC) [no. BB/J01446X/1]. Funding from Ministry of Economy and competitiveness, Spain [no. SAF2012-37979-C03-01] is also acknowledged.
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/12954

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