Our primary goal has been to discover
leukotriene biosynthesis inhibitors with characteristics that are appropriate for use as clinical agents. 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-lipoxygenase inhibitors as longer-acting compounds with good lung penetration. A variety of in vitro and in vivo methods were used to evaluate a large number of compounds, from which
ABT-761 [(R)-N-(3-(5-(4-fluorophenylmethyl)thien-2-yl)-1-methyl-2-pr opynyl)-N-
hydroxyurea] was selected for study.
ABT-761 exhibited potent and selective inhibition of
leukotriene formation both in vitro and in vivo. More importantly, the compound potently inhibited
antigen-induced
bronchospasm in guinea pigs when given either prophylactically or therapeutically. In addition,
ABT-761 was a potent inhibitor of eosinophil influx into the lungs of Brown Norway rats. These data provide added support for the role of
leukotrienes in both
bronchospasm and eosinophilic
inflammation and characterize
ABT-761 as a particularly potent inhibitor of
leukotrienes formed in pulmonary tissues. These data combined with the excellent pharmacokinetic characteristics of the compound indicate its potential use in the treatment of
leukotriene-dependent human disease.