RESUMEN
5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors. The optimization of the series to yield compounds with cell activity and brain permeability is described.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Oxazoles/química , Oxazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Trastorno Bipolar/tratamiento farmacológico , Encéfalo/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Modelos Moleculares , Oxazoles/síntesis química , Oxazoles/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3ß inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/farmacología , Tiofenos/farmacología , Línea Celular , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3 beta , Humanos , Modelos Moleculares , Estructura Molecular , Permeabilidad/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridonas/síntesis química , Piridonas/química , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
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.