title: Development of selective tight-binding inhibitors of leukotriene A4 hydrolase.
abstract: Leukotriene A4 hydrolase is a zinc-containing enzyme which exhibits both epoxide hydrolase and aminopeptidase activities. Since the enzyme product leukotriene B4 is an inflammatory mediator, it is of interest to develop selective inhibitors of leukotriene A4 hydrolase as potential antiinflammatory agents and as mechanistic probes. A systematic study on the enzyme specificity and the inhibition of its amidase activity with more than 30 synthetic inhibitors has led to the development of an alpha-keto-beta-amino ester (26) and a thioamine (27) as tight-binding, competitive type transition-state analog inhibitors of the aminopeptidase activity, with Ki values of 46 and 18 nM, respectively. Both compounds also inhibit the epoxide hydrolase activity, with the IC50 values of 1 microM and 0.1 microM for 26 and 27, respectively.
authors.affiliation: Department of Chemistry, Scripps Research Institute, La Jolla, California 92037.
authors.forename: W
authors.initials: W
authors.lastname: Yuan
authors.forename: B
authors.initials: B
authors.lastname: Munoz
authors.forename: C H
authors.initials: CH
authors.lastname: Wong
authors.forename: J Z
authors.initials: JZ
authors.lastname: Haeggström
authors.forename: A
authors.initials: A
authors.lastname: Wetterholm
authors.forename: B
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase