Synthesis and pharmacological evaluation of some 8-cyarropyrido[3 ',2 ': 4,5]thieno[3,2-d]triazine derivatives as inhibitors of nitric oxide and eicosanoid biosynthesis

A series of 8-cyanopyrido[3',2':4,5]thieno[3,2-d]-1,2,3-triazines, substitu ted at C-4 and C-7, were synthesized and evaluated as nitric oxide and pros taglandin E-2 inhibitors in murine peritoneal macrophages stimulated with b acterial endotoxin. Several compounds exhibited considerable activity, comp ounds 10 and 13 being the most interesting ones with IC50 values of 11.2 an d 3.4 on nitrites and 0.9 and 0.6 mu M on prostaglandin E-2 production, res pectively. None of the examples of pyridothienotriazines that were active a t 10 mu M showed any effect on inducible nitric oxide synthase, cyclooxygen ase-2, and cyclooxygenase-l enzymes, suggesting that they act by modifiying the level of expression of these inducible enzymes.