Characterization of A-93178, an Iminoxy-Quinoline

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protein (FLAP).⁵ Three compounds with this mechanism have reached the clinic but all three have apparently been withdrawn.⁴ We have synthesized a number of leukotriene inhibitors that are not direct inhibitors of 5-lipoxygenase with optimized pharmacokinetic and pharmacological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.