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1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological evaluation

AuthorsVenter, Jana; Pérez, Concepción; van Otterlo, Willem A. L.; Martínez, Ana ; Blackie, Margaret A.L.
KeywordsGlycogen synthase kinase 3
Alzheimer’s disease
Targeted covalent inhibitor
Cysteine 199
Issue Date29-Apr-2019
CitationBioorganic & Medicinal Chemistry Letters 29 (13)1597-1600 (2019)
AbstractGlycogen synthase kinase 3 (GSK-3) has become known for its multifactorial involvement in the pathogenesis of Alzheimer’s disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3β, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC50 = 0.086 ± 0.023 µM) and halomethylketone-substituted benzimidazolylurea 9b (IC50 = 0.13 ± 0.060 µM) displayed high GSK-3β inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC50 = 0.072 ± 0.043) in our assay. The results suggest further investigation of 2b and 9b as potential covalent inhibitors of GSK-3β, since a targeted interaction might provide improved kinase-selectivity.
Description4 p.-4 fig.-1 tab.
Publisher version (URL)https://doi.org/10.1016/j.bmcl.2019.04.049
Appears in Collections:(CIB) Artículos
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