The 5-lipoxygenase-activating protein (FLAP), an integral membrane protein, facilitates substrate transfer to 5-lipoxygenase which catalyzes leukotriene formation from arachidonic acid, making it an alternative target (in addition to 5-lipoxygenase) to intervene with leukotriene biosynthesis and respective diseases. MK-886, a potent FLAP inhibitor, potently suppresses leukotriene biosynthesis in intact leukocytes with an IC50 of 2.5 nM. Moreover, MK-886 concentration-dependently inhibited COX-1 with an IC50 of 8 μM. In platelets, MK-886 concentration-dependently suppressed the formation of the COX-1-derived products 12-HHT and TxB2 with IC50 values of 13 – 15 μM. Further, 10 μM MK-886 decreased platelet aggregation in washed platelets evoked by collagen or arachidonic acid[3]. In vitro, MK-886 increased GluR1 phosphorylation at both serine 831 and serine 845. In vivo, repeated daily i.p. injections of MK-886 resulted in increased GluR1 phosphorylation in brain samples obtained from the prefrontal cortex supporting the use of MK-886 as a pharmacological tool in studies of not only the 5-LOX pathway but also neuronal GluR1 functioning[4].
搜索
