Mode of action of the leukotriene synthesis (FLAP) inhibitor BAY X 1005: implications for biological regulation of 5-lipoxygenase.
Five-lipoxygenase (5-LOX) inhibition is gaining increasing importance as a novel approach to therapy of allergic asthma and other inflammatory diseases. Presently, two types of inhibitors are known, direct 5-LOX inhibitors (LOI) and the FLAP (five lipoxygenase activating protein) binding leukotriene synthesis inhibitors (LSI). The 5-LOX selective and orally active quinoline LSI, BAY X 1005, shares many mechanistic features with the indole LSI, MK-886. The binding of BAY X 1005 to FLAP correlates with LTB4 synthesis inhibition. BAY X 1005 has been shown to bind to the 18 kD protein FLAP. BAY X 1005 inhibits 5-LOX translocation from the cytosol to membranes and reverses 5-LOX translocation. The use of BAY X 1005 has helped to elucidate part of the complex FLAP/5-LOX interaction by showing that FLAP appears to represent a 5-LOX substrate transfer protein channelling endogenous and exogenous arachidonic acid to the leukotriene synthetizing 5-LOX. This notion presented by our group in 1992 has stimulated further mechanistic studies. These findings have additionally led to the hypothesis that substrate competition is not confined to the LSI/FLAP interaction but may also be true for the LOI/5-LOX interaction and that even mixed LSI/LOI 5-LOX inhibitors are feasible, yet have not been described. Further mechanistic work on LSI will be orientated not only to further elucidate the complex FLAP/5-LOX interaction, but also to identify FLAP-related eicosanoid binding proteins.
Hatzelmann
A
A
Bayer AG, Pharma Research Center, Wuppertal, Germany.
Fruchtmann
R
R
Mohrs
K H
KH
Raddatz
S
S
Matzke
M
M
Pleiss
U
U
Keldenich
J
J
Müller-Peddinghaus
R
R
D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis* / Q000187:drug effects; D001667:Binding, Competitive; D006801:Humans; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D011804:Quinolines / Q000494:pharmacology*
D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D001094:Arachidonate 5-Lipoxygenase