RESUMO
Inhibitors of p38 mitogen-activated protein (MAP) kinase, which are closely involved in the production of inflammatory cytokines, are considered promising curative drugs for chronic inflammatory disorders. However, there is also a growing concern regarding its systemic side effects. To reduce the occurrence of side effects, we have identified a novel p38 MAP kinase inhibitor that shows properties of an antedrug, which imparts its effect solely on the inflammatory site and is metabolically inactivated right after. We have designed isoxazole derivatives through the addition of a fresh interacting fourth site to the structure of the prototypical p38 MAP kinase inhibitor that harbors three point interactive sites. The derivative 26d (AKP-001) shows excellent p38 MAP kinase inhibitory activity and a high selectivity for various kinases. Its rapid metabolism has been confirmed in rats. Moreover, 26d has been shown to be effective in animal models of inflammatory bowel disease.
Assuntos
Desenho de Fármacos , Isoxazóis/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Sítios de Ligação , Linhagem Celular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Feminino , Meia-Vida , Humanos , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Fígado/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
A 55-year-old man was admitted to our hospital with dyspnea on effort and sclerodactyly. The chest radiograph showed reticulonodular shadows in both lower lung fields. A diagnosis of systemic sclerosis was made based on the characteristic skin lesions, interstitial pneumonia and the positivity for anti-Scl-70 antibody. Surgical biopsies were performed, which showed various features characteristic of organizing pneumonia and non-specific interstitial pneumonia. Prednisolone and cyclophosphamide were given to the patient, but clinical symptoms and chest radiographic findings worsened. After cyclophosphamide was replaced with cyclosporine, his symptoms, chest radiographic findings and pulmonary function improved and stabilized. It is suggested that cyclosporine is useful for the treatment of progressive interstitial pneumonia associated with systemic sclerosis.
