The combination of a 5phenylpyridine substituent and a novel, substituted thiopyrano[2,3,4 c,d]indole ring system yields a potent and selective 5lipoxygenase inhibitor, L-689,065.It has recently been established that 5-lipoxygenase (5-LO) inhibitors and leukotriene D4 antagonists are clinically effective in treating asthma. In addition, leukotrienes have been implicated in other disease states such as inflammatory bowel disease, psoriasis and rheumatoid arthritis. Thus the inhibition of the biosynthesis of leukotrienes by blocking the action of 5-LO, the first dedicated enzyme in the leukotriene cascade, may also provide a therapy for these diseases. Specific inhibitors of leukotriene biosynthesis can be divided into two classes: those that act by inhibiting 5-LO (direct inhibitors) and those that act by binding to 5-lipoxygenase activating protein (FLAP) thereby inhibiting the translocation of 5-LO to the membrane (indirect inhibitors). We have pioneered the latter approach which has led to the development of MK-0591, a potent and orally active FLAP inhibitor which is currently undergoing clinical evaluation. During the development of MK-0591 it was noticed that, in addition to binding to FLAP , some analogues were weak inhibitors of 5-LO activity. In this paper we describe how the judicious combination of structural features has led to the evolution of a new class of selective, direct 5-LO inhibitors from our indirect FLAP series of leukotriene biosynthesis inhibitors. This new class of 5-LO inhibitors are potent, bioavailable and functionally active.