RESUMO
Previously we reported the identification of RPR200765A, a potent orally bioavailable pyridine-imidazole inhibitor of p38 mitogen-activated protein (MAP) kinase which suppressed paw swelling and joint pathology in streptococcal cell wall-induced arthritis. Herein, we report the use of solid-phase combinatorial organic synthesis for the parallel processing of a related pyrimidine-imidazole-based library with two points of structural variability. We report also that the application of a computer algorithm, the Monte Carlo Monomer Selection, maximized both the combinatorial synthetic efficiency and the bioavailability of the final compounds. In conjunction with the synthetic protocols, the polymer-supported quench technique was applied to the purification of the final compounds. Through rapid evaluation of the library using a p38 kinase assay and permeability assays, it was possible to identify a number of potent and orally bioavailable p38 MAP kinase inhibitors suitable for further biological investigation.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Dioxanos/síntese química , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Piperazinas/síntese química , Pirimidinas/síntese química , Administração Oral , Algoritmos , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/sangue , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular , Técnicas de Química Combinatória , Dioxanos/farmacocinética , Dioxanos/farmacologia , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/metabolismo , Método de Monte Carlo , Piperazinas/farmacocinética , Piperazinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Plasma levels of some arachidonic acid metabolites were investigated in acute and chronic models of inflammation in rats. As a model of chronic inflammation, adjuvant arthritis in rats induced by the injection of Freund's complete adjuvant, and as an acute model for inflammation, kaolin-induced paw oedama were used. Plasma leukotriene(LT) C4-like and prostaglandin(PG) E2-like activities were quantitated by bioassay in guinea-pig ileum and rat stomach fundus respectively. In the course of adjuvant arthritis, plasma levels of LTC4- and PGEi2-like activities were increased. Plasma LTC4-like activity reached a maximum within 3 weeks, while PGE2-like activity reached a maximum 10 days after adjuvant injection. In the early phase of adjuvant arthritis, levels of both LTC4- and PGE2-like activities were found to be low but both activities were increased in the late phase of inflammation.