STRUCTURE-ACTIVITY-RELATIONSHIPS OF N-HYDROXYUREA 5-LIPOXYGENASE INHIBITORS

The discovery of second generation N-hydroxyurea 5-lipoxygenase inhibi tors was accomplished through the development of a broad structure-act ivity relationship (SAR) study. This study identified requirements for improving potency and also extending duration by limiting metabolism. Potency could be maintained by the incorporation of heterocyclic temp lates substituted with selected lipophilic substituents. Duration of i nhibition after oral administration was optimized by identification of structural features in the proximity of the N-hydroxyurea which corre lated to low in vitro glucuronidation rates. Furthermore, the rate of in vitro glucuronidation was shown to be stereoselective for certain a nalogs. Fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N-hy- droxyurea ( 17c) was identified and selected for clinical development.