A series of 8-cyanopyrido[3',2':4,5]thieno[3,2-d]-1,2,3-triazines, substituted at C-4 and C-7, were synthesized and evaluated as nitric oxide and prostaglandin E(2) inhibitors in murine peritoneal macrophages stimulated with bacterial endotoxin. Several compounds exhibited considerable activity, compounds 10 and 13 being the most interesting ones with IC(50) values of 11.2 and 3.4 microM on nitrites and 0.9 and 0.6 microM on prostaglandin E(2) production, respectively. None of the examples of pyridothienotriazines that were active at 10 microM showed any effect on inducible nitric oxide synthase, cyclooxygenase-2, and cyclooxygenase-1 enzymes, suggesting that they act by modifiying the level of expression of these inducible enzymes.