Leukotriene biosynthesis inhibition by aryl and aroyl substituted naphthoquinones

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 potent in vitro inhibition of 5-LO (IC50's less than 10(-6) M) and at doses of 1 mg/kg iv completely inhibited LTB4 production measured in ex vivo A23187-stimulated blood from dogs. The duration of action measured by the ex vivo assay was improved up to threefold over CGS 8515.