SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF TRIAZOLO[1,5-A]TRIAZINE DERIVATIVES INHIBITING EOSINOPHILIA

In continuation of our previous work on eosinophilia inhibitors, we sy nthesized an additional series of inhibitors, which consisted of no-1- [(methylamino)thiocarbonyl]-1H-1,2,4-triazole derivatives and a newly developed series of 1,2,4-triazololo[1,5-a]-1,3,5-triazine derivatives . We evaluated their inhibitory activity on the airway eosinophilia mo del, which was induced by the intravenous (iv) injection of Sephadex p articles. In the 1,2,4-triazole series with various substituents at th e 3 position of the triazole ring such as 2-furyl, pyridyl, and phenox y, none of derivatives had comparable activity to the previously repor ted compound GCC-AP0341, )-1-[(methylamino)thiocarbonyl]-1H-1,2,4-tria zole. In the triazolo[1,5-a]triazine series, methyl-1,2,4-triazolo[1,5 -a]-1,3,5-triazine-7(6H)- thione (3h) was highly potent, and when give n orally it had an ID50 value of 0.3 mg/kg, which is comparable to tha t of GCC-AP0341. The fact that the structure-activity relationship of these two series was quite similar suggests that a common substructure , such as the 1,2,4-triazole ring with a substituted phenyl ring at th e 3 position and a thiocarbonyl moiety at the 1 position, could contri bute to the activity. Our selected compound 3h was less active than GC C-AP0341 in the antigen-induced hyper-responsiveness model in guinea p igs; however, we plan to carry out further studies on eosinophil funct ions, especially on their activation, using our two compounds, 3h and GCC-AP0341.