RESUMEN
The biphenyl amides (BPAs) are a novel series of p38alpha MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Benzamidas/sangre , Benzamidas/química , Compuestos de Bifenilo/sangre , Compuestos de Bifenilo/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Conformación Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/química , RatasRESUMEN
The biphenyl amides are a novel series of p38 MAP kinase inhibitors. Structure-activity relationships of the series against p38alpha are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model.
Asunto(s)
Amidas/farmacología , Compuestos de Bifenilo/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Administración Oral , Amidas/química , Amidas/farmacocinética , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Oxadiazoles/química , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacología , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Recent innovations in drug therapies have made it highly desirable to obtain sensitive biomarkers of disease progression that can be used to quantify the performance of candidate disease modifying drugs. In order to measure potential image-based biomarkers of disease progression in an experimental model of rheumatoid arthritis (RA), we present two different methods to automatically quantify changes in a bone in in-vivo serial magnetic resonance (MR) images from the model. Both methods are based on rigid and nonrigid image registration to perform the analysis. The first method uses segmentation propagation to delineate a bone from the serial MR images giving a global measure of temporal changes in bone volume. The second method uses rigid body registration to determine intensity change within a bone, and then maps these into a reference coordinate system using nonrigid registration. This gives a local measure of temporal changes in bone lesion volume. We detected significant temporal changes in local bone lesion volume in five out of eight identified candidate bone lesion regions, and significant difference in local bone lesion volume between male and female subjects in three out of eight candidate bone lesion regions. But the global bone volume was found to be fluctuating over time. Finally, we compare our findings with histology of the subjects and the manual segmentation of bone lesions.