DEVELOPMENT OF SELECTIVE TIGHT-BINDING INHIBITORS OF LEUKOTRIENE-A4 HYDROLASE

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 K(i) values of 46 and 18 nM, respectively. Both compounds also inhibit the epoxide hydrolase activity, with the IC50 values of 1 muM and 0.1 muM for 26 and 27, respectively.