RESUMEN
Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.
Asunto(s)
Benzamidas/farmacología , Química Farmacéutica/métodos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/farmacología , Piperidonas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Simulación por Computador , Cristalografía por Rayos X/métodos , Citocinas/metabolismo , Diseño de Fármacos , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Humanos , Modelos Químicos , Chaperonas Moleculares , Fosforilación , Pirroles/químicaRESUMEN
MK2 kinase is a promising drug discovery target for the treatment of inflammatory diseases. Here, we describe the discovery of novel MK2 inhibitors using X-ray crystallography and structure-based drug design. The lead has in vivo efficacy in a short-term preclinical model.
Asunto(s)
Adenosina Trifosfato , Diseño de Fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Unión Competitiva , Células CACO-2 , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Humanos , Concentración 50 Inhibidora , Péptidos y Proteínas de Señalización Intracelular/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/química , Ratas , Relación Estructura-ActividadRESUMEN
To achieve good mechanical properties of carbon fibre-reinforced polycarbonate composites, the fibre-matrix adhesion must be dialled to an optimum level. The electrolytic surface treatment of carbon fibres during their production is one of the possible means of adapting the surface characteristics of the fibres. The production of a range of tailored fibres with varying surface treatments (adjusting the current, potential, and conductivity) was followed by contact angle, inverse gas chromatography and X-ray photoelectron spectroscopy measurements, which revealed a significant increase in polarity and hydroxyl, carboxyl, and nitrile groups on the fibre surface. Accordingly, an increase in the fibre-matrix interaction indicated by a higher interfacial shear strength was observed with the single fibre pull-out force-displacement curves. The statistical analysis identified the correlation between the process settings, fibre surface characteristics, and the performance of the fibres during single fibre pull-out testing.