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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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Author(s)

Ondrej Benek, Lukas Hroch, Laura Aitken, Frank Gunn-Moore, Lucie Vinklarova, Kamil Kuca, Daniel I. Perez, Concepcion Perez, Ana Martinez, Zdenek Fisar, Kamil Musilek

School/Research organisations

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.
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Details

Original languageEnglish
Pages (from-to)665-670
Number of pages6
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume33
Issue number1
Early online date14 Mar 2018
DOIs
Publication statusPublished - 2018

    Research areas

  • Alzheimer's disease, Amyloid-beta binding alcohol dehydrogenase (ABAD), Benzothiazole, Casein kinase 1 (CK1), Neurodegeneration

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