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Molecules ; 23(2)2018 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-29364148

RESUMEN

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a potential drug target because of its role in the development of Down syndrome and Alzheimer's disease. The selective DYRK1A inhibitor 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal194), a large, flat and lipophilic molecule, suffers from poor water solubility, limiting its use as chemical probe in cellular assays and animal models. Based on the structure of KuFal194, 7-chloro-1H-indole-3-carbonitrile was selected as fragment template for the development of smaller and less lipophilic DYRK1A inhibitors. By modification of this fragment, a series of indole-3-carbonitriles was designed and evaluated as potential DYRK1A ligands by molecular docking studies. Synthesis and in vitro assays on DYRK1A and related protein kinases identified novel double-digit nanomolar inhibitors with submicromolar activity in cell culture assays.


Asunto(s)
Diseño de Fármacos , Indoles/química , Nitrilos/química , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Activación Enzimática/efectos de los fármacos , Concentración 50 Inhibidora , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Nitrilos/síntesis química , Proteínas Serina-Treonina Quinasas/química , Proteínas Tirosina Quinasas/química , Solubilidad , Quinasas DyrK
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