RESUMEN
Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Quinasa 1 de Quinasa de Quinasa MAP , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Urea/análogos & derivados , Urea/farmacología , Amidas/síntesis química , Amidas/farmacología , Baculoviridae/genética , Inhibidores Enzimáticos/síntesis química , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Solubilidad , Relación Estructura-Actividad , Urea/síntesis químicaRESUMEN
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).