RESUMO
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.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/química , Relação Quantitativa Estrutura-Atividade , Animais , Ligação Competitiva/efeitos dos fármacos , Camundongos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacologia , Quinases DyrkRESUMO
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.
Assuntos
Síndrome de Down/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Aminoácidos/química , Animais , Sítios de Ligação , Modelos Animais de Doenças , Síndrome de Down/fisiopatologia , Inibidores Enzimáticos/isolamento & purificação , Humanos , Ligação de Hidrogênio , Deficiências da Aprendizagem/tratamento farmacológico , Deficiências da Aprendizagem/fisiopatologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Camundongos , Estrutura Molecular , Quinases DyrkRESUMO
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.
