RESUMEN
p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.
Asunto(s)
Proteína de Unión a CREB/antagonistas & inhibidores , Descubrimiento de Drogas , Proteína p300 Asociada a E1A/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Hidantoínas/farmacología , Compuestos de Espiro/farmacología , Administración Oral , Disponibilidad Biológica , Proteína de Unión a CREB/metabolismo , Relación Dosis-Respuesta a Droga , Proteína p300 Asociada a E1A/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/metabolismo , Humanos , Hidantoínas/administración & dosificación , Hidantoínas/metabolismo , Estructura Molecular , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 5-methoxy- and 5-hydroxy-6-fluoro-1,8-naphthyridone-3-carboxylic acid derivatives were prepared and evaluated for cell-free bacterial protein synthesis inhibition and whole cell antibacterial activity. When compared to the analogous 5-hydrogen compounds, the presence of the 5-OH group negatively affects biochemical potency. However, a tolerance of the 5-methoxy group is indicated. Only moderate whole cell antibacterial activity is seen, but this could be due to poor cellular penetration. Because only a few 7-position variants were made for this study, further investigation into this novel series combining a broader range of 7-amino derivatives with these 5-position modifications is warranted.