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J Med Chem. 2004 Feb 12;47(4):1044-50.

Inhibition of adenosine deaminase by novel 5:7 fused heterocycles containing the imidazo[4,5-e][1,2,4]triazepine ring system: a structure-activity relationship study.

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Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.


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.

[Indexed for MEDLINE]

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