title: 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.
abstract: 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.
authors.affiliation: Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.
authors.forename: Ayub
authors.initials: A
authors.lastname: Reayi
authors.forename: Ramachandra S
authors.initials: RS
authors.lastname: Hosmane
mesh_terms: D000241:Adenosine / Q000737:chemistry; D000243:Adenosine Deaminase / Q000737:chemistry; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry; D002417:Cattle; D006868:Hydrolysis; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D013329:Structure-Activity Relationship
chemical_list: D058892:Adenosine Deaminase Inhibitors; D001381:Azepines; D007093:Imidazoles; D000243:Adenosine Deaminase; D000241:Adenosine