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.
Eur J Med Chem
; 158: 270-285, 2018 Oct 05.
Article
en En
| MEDLINE
| ID: mdl-30223116
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 Dyrk1Aâ¯=â¯3.2â¯nM; Dyrk1Bâ¯=â¯72.9â¯nM and Clk1â¯=â¯270â¯nM) and inhibited the Dyrk1A activity in HeLa cells with high efficacy (IC50 43â¯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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tiofenos
/
Proteínas Tirosina Quinasas
/
Proteínas Serina-Treonina Quinasas
/
Inhibidores de Proteínas Quinasas
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2018
Tipo del documento:
Article
País de afiliación:
Egipto