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

J Med Chem. 2004 Feb 12;47(4):1044-50. doi: 10.1021/jm0304257.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine / chemistry
  • Adenosine Deaminase / chemistry
  • Adenosine Deaminase Inhibitors*
  • Animals
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Cattle
  • Hydrolysis
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Kinetics
  • Structure-Activity Relationship


  • Adenosine Deaminase Inhibitors
  • Azepines
  • Imidazoles
  • Adenosine Deaminase
  • Adenosine