ABSTRACT
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.
Subject(s)
NF-kappa B/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Transcription Factor AP-1/antagonists & inhibitors , Transcriptional Activation/drug effects , Administration, Oral , Animals , Arthritis, Experimental/drug therapy , Disease Models, Animal , Drug Design , Humans , Jurkat Cells , Quinazolines/administration & dosage , Rats , Structure-Activity RelationshipABSTRACT
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.
