RESUMO
We have developed novel orally active quinazoline analogues as inhibitors of AP-1 and NF-kappaB mediated transcriptional activation. Among the derivatives prepared, 1-[2-(2-thienyl)quinazolin-4-ylamino]-3-methyl-3-pyrroline-2,5-dione (10) showed significant activity in an adjuvant-induced arthritis rat model by reducing the swelling by 65% in the non-injected foot. The synthesis, structure-activity relationship, and in vivo activity are described.
Assuntos
NF-kappa B/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Fator de Transcrição AP-1/antagonistas & inibidores , Ativação Transcricional/efeitos dos fármacos , Administração Oral , Animais , Artrite Experimental/tratamento farmacológico , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Células Jurkat , Quinazolinas/administração & dosagem , Ratos , Relação Estrutura-AtividadeRESUMO
Several analogues of ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (1) were synthesized and tested as inhibitors of AP-1 and NF-kappaB mediated transcriptional activation in Jurkat T cells. From our SAR work, ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))-N-methylamino]-4-(trifluoromethyl)-pyrimidine-5-carboxylate was identified as a novel and potent inhibitor.