RESUMEN
Individuals with Down syndrome (DS) suffer from mental retardation. Overexpression and the resulting increased specific activity of Dyrk1A kinase located on chromosome 21 cause a learning and memory deficit in Dyrk1A transgenic mice. To search for therapeutic agents with Dyrk1A inhibition activity, previously we obtained HCD160 as a new hit compound for Dyrk1A inhibition. In the present study, we synthesized 34 HCD160 derivatives to investigate the quantitative structure-activity relationship (QSAR). This analysis could provide important information for novel drug discovery for treatment of DS related learning and memory deficits.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/química , Relación Estructura-Actividad Cuantitativa , Animales , Unión Competitiva/efectos de los fármacos , Ratones , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Pirazoles/metabolismo , Pirazoles/farmacología , Quinasas DyrKRESUMEN
Mental retardation is the most common and debilitating condition for individuals with Down syndrome (DS). The hyper-activation of DYRK1A by overexpression causes significant learning and memory deficits in DS-model mice. Thus far, no mechanism-based drug has been developed to address this. After a combination of in silico and in vitro screenings, two DYRK1A inhibitors were isolated that are active in a cell-based assay. Further optimization could lead to a novel drug discovery that could address DS learning and memory deficits.
Asunto(s)
Síndrome de Down/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Aminoácidos/química , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Inhibidores Enzimáticos/aislamiento & purificación , Humanos , Enlace de Hidrógeno , Discapacidades para el Aprendizaje/tratamiento farmacológico , Discapacidades para el Aprendizaje/fisiopatología , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/fisiopatología , Ratones , Estructura Molecular , Quinasas DyrKRESUMEN
We report the solid-phase library construction of 2000 analogues of 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran. The polymer-bound hydroxyalkoxychromanes 5, produced by nucleophilic reactions with various alcohols on epoxides generated in situ, served as key intermediates for subsequent diversification. Further reactions on these hydroxyalkoxychromanes 5 with various electrophiles, such as alkyl halides and acid halides, produced the desired 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran analogues 9, 10, and 11. The progress of reactions could be monitored as solid-bound intermediates by ATR-FTIR or HR-MAS-NMR spectroscopy. The final compounds, obtained in good yields and high purity upon cleavage from the resins, were characterized by LC/MS, HRMS, (1)H NMR, and (13)C NMR spectroscopy.