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

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Hatzelmann A, Fruchtmann R, Mohrs KH, Raddatz S, Matzke M, Pleiss U, Keldenich J, Muller-Peddinghaus R

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

Agents Actions. 1994 Nov;43(1-2):64-8. doi: 10.1007/BF02005767.

PubMed ID

7741044 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Veliflapon	Arachidonate 5-lipoxygenase-activating protein	Protein	Humans	Yes	Inhibitor	Details