1.
Bioorg Med Chem Lett
; 21(15): 4507-11, 2011 Aug 01.
Artículo
en Inglés
| MEDLINE
| ID: mdl-21723120
RESUMEN
The synthesis and SAR of a series of novel pyrazolo-quinazolines as potent and selective MPS1 inhibitors are reported. We describe the optimization of the initial hit, identified by screening the internal library collection, into an orally available, potent and selective MPS1 inhibitor.
Asunto(s)
Amidas/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas/química , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Animales , Proteínas de Ciclo Celular/metabolismo , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett
; 20(14): 4095-9, 2010 Jul 15.
Artículo
en Inglés
| MEDLINE
| ID: mdl-20621725
RESUMEN
In this Letter is described the structure-based design of potent dihydro-pyrazoloquinazolines as PDK1 inhibitors. Starting from low potency HTS hits with the aid of X-ray crystallography and modeling, a medicinal chemistry activity was carried out to improve potency versus PDK1 and selectivity versus CDK2 protein kinase.