Zileuton (A-64077) was the first 5-lipoxygenase inhibitor of the N-hydroxyurea class selected as an investigational new drug for the treatment of leukotriene mediated diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis. Clinical results with zileuton in asthma have demonstrated efficacy for this new therapeutic approach. Continuing research has focused on the discovery of second generation inhibitors with improved potency and duration of action. A strategy was

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... d for the N-hydroxyurea series involving substantial synthetic throughput to evaluate key structural elements of a simple inhibitor model with respect to inhibitory activity, oral bioavailability, and rate of metabolism. This approach culminated in the identification of A-78773, an optimized second-generation 5-lipoxygenase inhibitor with improved in vivo potency and significantly longer plasma half-life in several species.