Leukotriene biosynthesis inhibition by aryl and aroyl substituted naphthoquinones
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Naphthoquinones are known to inhibit 5-lipoxygenase. In particular, CGS 8515 (methyl 2-[(3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino]benzoate) has been studied in detail. However this potent and selective 5-lipoxygenase inhibitor has a short duration of action and poor bioavailability. To improve the duration of action we have prepared a series of carbon substituted naphthoquinones. Several members of this series have demonstrated potentin vitro inhibition of 5-LO (IC50's<10−6M) and at doses of 1 mg/kg iv completely inhibited LTB4 production measured inex vivo A23187-stimulated blood from dogs. The duration of action measured by theex vivo assay was improved up to threefold over CGS 8515.
KeywordsMethyl Short Duration LTB4 Naphthoquinones Biosynthesis Inhibition
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- E. F. Kimble, D. H. White, W. H. Lee, E. C. Ku and T. D. Oglesby,Biochemical evaluation of 5-lipoxygenase in the beagle dog in vitro and ex vivo. 4th International Conference, Inflammation Research Association: Poster #87 (1988).Google Scholar