Please use this identifier to cite or link to this item: doi:10.22028/D291-29391
Volltext verfügbar? / Dokumentlieferung
Title: Development of novel amide-derivatized 2,4-bispyridyl thiophenes as highly potent and selective Dyrk1A inhibitors. Part II : Identification of the cyclopropylamide moiety as a key modification
Author(s): Darwish, Sarah S.
Abdel-Halim, Mohammad
ElHady, Ahmed K.
Salah, Mohamed
Abadi, Ashraf H.
Becker, Walter
Engel, Matthias
Language: English
Title: European journal of medicinal chemistry
Volume: 158
Startpage: 270
Endpage: 285
Publisher/Platform: Elsevier
Year of Publication: 2018
Publikation type: Journal Article
Abstract: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a potential target in Alzheimer's disease (AD) because of the established correlation between its over-expression and generation of neurofibrillary tangles (NFT) as well as the accumulation of amyloid plaques. However, the use of Dyrk1A inhibitors requires a high degree of selectivity over closely related kinases. In addition, the physicochemical properties of the Dyrk1A inhibitors need to be controlled to enable CNS permeability. In the present study, we optimized our previously published 2,4-bispyridyl thiophene class of Dyrk1A inhibitors by the synthesis of a small library of amide derivatives, carrying alkyl, cycloalkyl, as well as acidic and basic residues. Among this library, the cyclopropylamido modification (compound 4b) was identified as being highly beneficial for several crucial properties. 4b displayed high potency and selectivity against Dyrk1A over closely related kinases in cell-free assays (IC50: Dyrk1A = 3.2 nM; Dyrk1B = 72.9 nM and Clk1 = 270 nM) and inhibited the Dyrk1A activity in HeLa cells with high efficacy (IC50: 43 nM), while no significant cytotoxicity was observed. In addition, the cyclopropylamido group conferred high metabolic stability and maintained the calculated physicochemical properties in a range compatible with a potential CNS activity. Thus, based on its favourable properties, 4b can be considered as a candidate for further in vivo testing in animal models of AD.
DOI of the first publication: 10.1016/j.ejmech.2018.08.097
Link to this record: hdl:20.500.11880/27872
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

Files for this record:
There are no files associated with this item.

Items in SciDok are protected by copyright, with all rights reserved, unless otherwise indicated.