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
4-Amino-5,6-diaryl-furo[2,3-d]pyrimidines have been identified as inhibitors of glycogen synthase kinase-3beta (GSK-3beta). One representative derivative, 4-amino-3-(4-(benzenesulfonylamino)-phenyl)-2-(3-pyridyl)-furo[2,3-d]pyrimidine (12) exhibited potent GSK-3beta inhibitory activity in low nanomolar level of IC(50). The binding mode was proposed from a docking study.
Asunto(s)
Diseño de Fármacos , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Polarización de Fluorescencia , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Modelos Químicos , Estructura Molecular , Receptor TIE-2/antagonistas & inhibidores , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
The temperature-dependences of the second-order rate constants (k) of the reactions of the catalytic site thiol groups of two cysteine peptidases papain (EC 3.4.22.2) and actinidin (EC 3.4.22.14) with a series of seven 2-pyridyl disulphide reactivity probes (R-S-S-2-Py, in which R provides variation in recognition features) were determined at pH 6.7 at temperatures in the range 4-30 degrees C by stopped-flow methodology and were used to calculate values of DeltaS++, DeltaH++ and DeltaG++. The marked changes in DeltaS++ from negative to positive in the papain reactions consequent on provision of increase in the opportunities for key non-covalent recognition interactions may implicate microsite desolvation in binding site-catalytic site signalling to provide a catalytically relevant transition state. The substantially different behaviour of actinidin including apparent masking of changes in DeltaH++ by an endothermic conformational change suggests a difference in mechanism involving kinetically significant conformational change.
Asunto(s)
Cisteína Endopeptidasas/metabolismo , Papaína/metabolismo , Catálisis , Dominio Catalítico , Cisteína Endopeptidasas/química , Disulfuros/química , Disulfuros/metabolismo , Concentración de Iones de Hidrógeno , Cinética , Papaína/química , Conformación Proteica , Relación Estructura-Actividad , Especificidad por Sustrato , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/metabolismo , TemperaturaRESUMEN
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.