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1.
Chem Commun (Camb) ; 59(34): 5071-5074, 2023 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-37021390

RESUMEN

We report that a selective fluorescent indicator NBD-NCD for UGGAA repeats resulted in fluorescence quenching upon binding to RNA and recovered the fluorescence by displacing NBD-NCD with UGGAA repeat-targeted small molecules. The fluorescent indicator displacement assay using NBD-NCD can detect the interaction of small molecules with UGGAA repeats.


Asunto(s)
Enfermedades no Transmisibles , Humanos , Colorantes Fluorescentes/química , ARN/química , Espectrometría de Fluorescencia
2.
Bioorg Med Chem Lett ; 27(16): 3733-3738, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28712706

RESUMEN

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3ß. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3ß respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3ß with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.


Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/farmacología , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-Actividad
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