RESUMEN
The discovery and hit-to-lead exploration of a novel series of selective IKK-ß kinase inhibitors is described. The initial lead fragment 3 was identified by pharmacophore-directed virtual screening. Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles.
Asunto(s)
Amidas/química , Quinasa I-kappa B/antagonistas & inhibidores , Indoles/química , Inhibidores de Proteínas Quinasas/química , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Animales , Sitios de Unión , Simulación por Computador , Evaluación Preclínica de Medicamentos , Humanos , Quinasa I-kappa B/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.