RESUMEN
Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC50â¯=â¯7.4/0.9â¯nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219. Overall, compound 10d could be a promising candidate and a good starting point as anticancer drugs.
Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Diseño de Fármacos , Imidazoles/farmacología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
We have identified a novel series of substituted N,N'-diarylurea p38α inhibitors. The inhibitory activity of the target compounds against the enzyme p38α, MAPKAPK2 in BHK cells, TNF-α release in LPS-stimulated THP-1 cells and p38α binding experiments were tested. Among these compounds, 25a inhibited the p38α enzyme with an IC50 value of 0.47 nM and a KD value of 1.54 × 10(-8) and appears to be the most promising one in the series.
Asunto(s)
Inhibidores Enzimáticos/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Urea/administración & dosificación , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Línea Celular Tumoral , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ligandos , Lipopolisacáridos/química , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/química , Urea/análogos & derivados , Urea/química , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
A novel series of substituted N,N'-diaryl ureas that act as p38α inhibitors have been designed and synthesized based on two key residues (Gly110 and Thr106) that are different in p38α MAPK than in other kinases. Preliminary biological evaluation indicated that most compounds possessed good p38α inhibitory potencies. Among these compounds, 9g appeared to be the most powerful and is the main compound that we will study in the future.