Design of inhibitors of leukotriene biosynthesis and their therapeutic potential

Abstract

Leukotrienes (LT) are biosynthetic products derived from arachidonic acid. Investigational drugs which inhibit the biosynthesis of LT or block the actions of LT at their receptors have shown therapeutic benefit in asthmatics. A new series of 2-quinolylmethoxyphenylalkyliminoxyalkylcarboxylates was discovered which blocked LT biosynthesis in intact cells but did not inhibit 5-LO catalysis. The mechanism of LT inhibition likely resulted from interfering with five-lipoxygenase activating protein (FLAP). The spatial arrangement and stereochemistry of groups proved important for inhibitory activity. A-93178.5 is an optimized leukotriene inhibitor with potent oral activity in several animal models.