Leukotrienes, prostaglandins and epoxyeicosatrienoic acids are specialized lipids that are derived from oxygenation of the polyunsaturated fatty acid arachidonic acid (AA) by 5-lipoxygenase (5-LO), cyclooxygenase (COX) or cytochrome P450 epoxygenase activity, respectively. Membrane-embedded FLAP selectively transfers AA to 5-LO and enhances the sequential oxygenation of AA to 5(S)-hydroperoxyeicosatetraenoic acid (5-HpETE) and dehydration to leukotriene A4 (LTA4). These are the only known roles for FLAP, and cellular leukotriene synthesis can be completely inhibited by compounds that bind to FLAP. Sophisticated GPCR signaling pathways for leukotrienes could have evolved from a basic anti-oxidant role; FLAP is a member of the MAPEG (membrane-associated proteins in eicosanoid-and-glutathione metabolism) superfamily, members of which typically have glutathione transferase activity. Unlike drugs targeting more ubiquitous inflammation pathways, such as the prostaglandin or tumor necrosis factor (TNF) pathways, no major side effects have been observed with chronic complete inhibition of leukotriene synthesis. Given that leukotrienes are deleterious in both the acute and chronic aspects of respiratory disease and CVD, the therapeutic potential of novel anti-inflammatory FLAP inhibitors is enormous.

References

1.Evans JF, et al. Trends Pharmacol Sci. 2008;29(2):72–78.