Mode of action of the leukotriene synthesis (FLAP) inhibitor BAY X 1005: implications for biological regulation of 5-lipoxygenase.

Abstract

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.

• Authors: A Hatzelmann, R Fruchtmann, K H Mohrs, S Raddatz, M Matzke, U Pleiss, J Keldenich, R Müller-Peddinghaus
• Journal: Agents and actions (Agents Actions) Vol. 43 Issue 1-2 Pg. 64-8 (Nov 1994) ISSN: 0065-4299 [Print] Switzerland
• PMID: 7741044 (Publication Type: Journal Article, Review)

Chemical References

• Leukotriene Antagonists
• Leukotrienes
• Quinolines
• 2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid
• Arachidonate 5-Lipoxygenase

Topics

• Arachidonate 5-Lipoxygenase (biosynthesis, drug effects)
• Binding, Competitive
• Humans
• Leukotriene Antagonists
• Leukotrienes (biosynthesis)
• Neutrophils (drug effects, enzymology)
• Quinolines (pharmacology)