HYL]-2-THIENYL]-1-METHYL-2-PROPYNYL]-N-HYDROXYUREA (ABT-761), A 2ND-GENERATION 5-LIPOXYGENASE INHIBITOR())

Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was condu cted. The lipophilic heteroaryl template and the link group connnectin g the template to the N-hydroxyurea pharmacophore were modified. Inhib ition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used t o evaluate congeners for comparative rates of glucuronidation. (3-Hete roaryl-1-methyl-2-propynyl)-N-hydroxyureas were found to be more resis tant to in vitro glucuronidation. The promising inhibitor henoxy)2-fur yl]-1-methyl-2-propynyl]-N-hydroxyurea (6) was found to have stereosel ective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood a ssay. Further optimization of the lipophilic template led to the disco very of hyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with m ore effective and prolonged inhibition of leukotriene biosynthesis tha n zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase i nhibitor 11 was selected for development as an investigational drug fo r leukotriene-mediated disorders.