ABT-761 ATTENUATES BRONCHOCONSTRICTION AND PULMONARY INFLAMMATION IN RODENTS

Our primary goal has been to discover leukotriene biosynthesis inhibit ors with characteristics that are appropriate for use as clinical agen ts. The success of the use of zileuton in the treatment of asthma led us to explore further the use of the N-hydroxyurea class of 5-lipoxyge nase inhibitors as longer-acting compounds with good lung penetration. A variety of in vitro and in vivo methods were used to evaluate a lar ge number of compounds, from which ABT-761 yl)thien-2-yl)-1-methyl-2-p ropynyl)-N-hydroxyurea] was selected for study, ABT-761 exhibited pote nt and selective inhibition of leukotriene formation both in vitro and in vivo. More importantly, the compound potently inhibited antigen-in duced bronchospasm in guinea pigs when given either prophylactically o r therapeutically. In addition, ABT-761 was a potent inhibitor of eosi nophil influx into the lungs of Brown Norway rats. These data provide added support for the role of leukotrienes in both bronchospasm and eo sinophilic inflammation and characterize ABT-761 as a particularly pot ent inhibitor of leukotrienes formed in pulmonary tissues. These data combined with the excellent pharmacokinetic characteristics of the com pound indicate its potential use in the treatment of leukotriene-depen dent human disease.