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 synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.
Asunto(s)
Química Farmacéutica/métodos , Quinasa I-kappa B/antagonistas & inhibidores , Indoles/síntesis química , Indoles/farmacología , Adenosina Trifosfato/química , Sitios de Unión , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.
Asunto(s)
Descubrimiento de Drogas , Quinasa I-kappa B/antagonistas & inhibidores , Isoquinolinas/química , Isoquinolinas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Humanos , Quinasa I-kappa B/química , Quinasa I-kappa B/metabolismo , Concentración 50 Inhibidora , Isoquinolinas/metabolismo , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteínas Quinasas/metabolismoRESUMEN
A potent and selective series of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta is described. The most potent compounds are 8h, 8r and 8v, with IKK-beta inhibitory potencies of pIC(50) 7.0, 6.8 and 6.8, respectively. The series has excellent selectivity, both within the IKK family over IKK-epsilon, and across a wide variety of kinase assays. The potency of 8h in the IKK-beta enzyme assay translates to significant cellular activity (pIC(50) 5.7-6.1) in assays of functional and mechanistic relevance.
Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Benzamidas/química , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Modelos MolecularesRESUMEN
The identification and hit-to-lead exploration of a novel, potent and selective series of substituted benzimidazole-thiophene carbonitrile inhibitors of IKK-epsilon kinase is described. Compound 12e was identified with an IKK-epsilon enzyme potency of pIC(50) 7.4, and has a highly encouraging wider selectivity profile, including selectivity within the IKK kinase family.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Enlace de Hidrógeno , Cinética , Modelos Moleculares , Tiofenos/química , Difracción de Rayos XRESUMEN
The discovery, synthesis, potential binding mode, and in vitro kinase profile of several pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines as potent kinase inhibitors are discussed.