Please use this identifier to cite or link to this item: doi:10.22028/D291-29394
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Title: Development of novel 2,4-bispyridyl thiophene-based compounds as highly potent and selective Dyrk1A inhibitors. Part I : Benzamide and benzylamide derivatives
Author(s): Darwish, Sarah S.
Abdel-Halim, Mohammad
Salah, Mohamed
Abadi, Ashraf H.
Becker, Walter
Engel, Matthias
Language: English
Title: European journal of medicinal chemistry
Volume: 157
Startpage: 1031
Endpage: 1050
Publisher/Platform: Elsevier
Year of Publication: 2018
Publikation type: Journal Article
Abstract: The protein kinase Dyrk1A modulates several processes relevant to the development or progression of Alzheimer's disease (AD), e. g. through phosphorylation of tau protein, amyloid precursor protein (APP) as well as proteins involved in the regulation of alternative splicing of tau pre-mRNA. Therefore, Dyrk1A has been proposed as a potential target for the treatment of AD. However, the co-inhibition of other closely related kinases of the same family of protein kinases (e.g. Dyrk1B and Dyrk2) or kinases from other families such as Clk1 limits the use of Dyrk1A inhibitors, as this may cause unpredictable side effects especially over long treatment periods. Herein, we describe the design and synthesis of a series of amide functionalized 2,4-bispyridyl thiophene compounds, of which the 4-fluorobenzyl amide derivative (31b) displayed the highest potency against Dyrk1A and remarkable selectivity over closely related kinases (IC50: Dyrk1A = 14.3 nM; Dyrk1B = 383 nM, Clk1 > 2 μM). This degree of selectivity over the frequently hit off-targets has rarely been achieved to date. Additionally, 31b inhibited Dyrk1A in intact cells with high efficacy (IC50 = 79 nM). Furthermore, 31b displayed a high metabolic stability in vitro with a half-life of 2 h. Altogether, the benzamide and benzylamide extension at the 2,4-bispyridyl thiophene core improved several key properties, giving access to compound suitable for future in vivo studies.
DOI of the first publication: 10.1016/j.ejmech.2018.07.050
Link to this record: hdl:20.500.11880/27873
ISSN: 1768-3254
Date of registration: 24-Sep-2019
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Pharmazie
Professorship: NT - Prof. Dr. Christian Ducho
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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