Structure-activity optimization of inhibitory potency and duration of action of A-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl templateand the link group connnecting the template to the IV-hydroxyurea pharmacophore were modified. Inhibition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation.(3-Heteroaryl-l-methyl-2-propynyl)-A-hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor A-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-A-hydroxyurea (6) was found to have stereoselective glucuronida-tion in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic templateled to the discovery of CR)-(+)-A-[3-[5-[(4-fluorophenyl) methyl]-2-thienyl]-l-methyl-2-propynyl]-A-hydroxyurea (11) with more effective and prolonged inhibition ofleukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene-mediateddisorders.