DESIGN OF INHIBITORS OF LEUKOTRIENE BIOSYNTHESIS AND THEIR THERAPEUTIC POTENTIAL

Leukotrienes (LT) are biosynthetic products derived from arachidonic a cid. Investigational drugs which inhibit the biosynthesis of LT or blo ck the actions of LT at their receptors have shown therapeutic benefit in asthmatics. A new series of 2-quinolylmethoxyphenylalkyliminoxyalk ylates was discovered which blocked LT biosynthesis in intact cells bu t did not inhibit 5-LO catalysis. The mechanism of LT inhibition likel y resulted from interfering with five-lipoxygenase activating protein (FLAP). The spatial arrangement and stereochemistry of groups proved i mportant for inhibitory activity. A-93178.5 is an optimized leukotrien e inhibitor with potent oral;activity in several animal models.