Characterization of A-93178, an iminoxy-quinoline inhibitor of leukotriene biosynthesis.

Abstract

In recent years a number of leukotriene modulators have shown promise in the treatment of asthma.1, 2 Most of these have been Cys-LT1 antagonists.2 Inhibitors of both cysteinyl leukotrienes and LTB4 however are likely to be more effective given the pro-inflammatory characteristics of LTB4. In addition, these inhibitors would also inhibit the formation of the mediators formed from double lipoxygenation such as lipoxins.3 Thus far, most bioavailable inhibitors of 5-lipoxygenase have been related to zileuton or ZD-2138.4 An alternative to 5-lipoxygenase inhibition is the antagonism of the 5-lipoxygenase activating protein (FLAP).5 Three compounds with this mechanism have reached the clinic but all three have apparently been withdrawn.4 We have synthesized a number of leukotriene inhibitors that are not direct inhibitors of 5-lipoxygenase with optimized pharmacokinetic and pharmacological characteristics. The best of these is A-93178.