As part of a program to explore structure-activity relationships for the extremely tight binding inhibition characteristics of coformycins to adenosine deaminase, a series of analogues (1a-1h) containing the imidazo[4,5-e][1,2,4]triazepine ring system has been synthesized and screened in vitro against a mammalian adenosine deaminase for inhibitory activity. While compounds 1a and 1b were synthesized in five steps starting from 4-nitroimidazole, others were derived from 1a through simple exchange reactions with the appropriate alcohols. The observed kinetics profiles and K(i) values suggest that the target compounds are competitive inhibitors that bind 6-9 orders of magnitude less tightly to the enzyme. Compounds 1c and 1d were the most active in the series with K(i)'s ranging from 12 to 15 microM.