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Journal of Enzyme Inhibition and Medicinal Chemistry
Article . 2018 . Peer-reviewed
License: CC BY
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PubMed Central
Article . 2018
License: CC BY
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St Andrews Research Repository
Article . 2018 . Peer-reviewed
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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

Authors: Ondrej Benek; Lukas Hroch; Laura Aitken; Frank Gunn-Moore; Lucie Vinklarova; Kamil Kuca; Daniel I. Perez; +4 Authors

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

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.

Country
United Kingdom
Keywords

QH301 Biology, Short Communication, NDAS, 610, RM1-950, Amyloid-beta binding alcohol dehydrogenase (ABAD), QH301, Structure-Activity Relationship, Humans, QD, Benzothiazoles, Neurodegeneration, Enzyme Inhibitors, Dose-Response Relationship, Drug, Molecular Structure, Casein Kinase I, Phenylurea Compounds, neurodegeneration, 3-Hydroxyacyl CoA Dehydrogenases, Neurodegenerative Diseases, benzothiazole, Alzheimer's disease, Benzothiazole, QD Chemistry, casein kinase 1 (CK1), Casein kinase 1 (CK1), RC0321, amyloid-beta binding alcohol dehydrogenase (ABAD), Therapeutics. Pharmacology, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Alzheimer’s disease

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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