Dual Inhibitors of Thromboxane A2 Synthase and 5-Lipoxygenase with Scavenging Activity of Active Oxygen Species. Synthesis of a Novel Series of (3-Pyridylmethyl)benzoquinone Derivatives

Article abstract of DOI:10.1021/jm00105a042

A novel series of (3-pyridylmethyl)benzoquinone derivatives was molecular designed and synthesized for the dual purpose of inhibiting thromboxane A₂ and leukotriene biosynthesis enzymes and scavenging active oxygen species (AOS).They were evaluated for inhibition of TXA₂ synthase, inhibition of 5-lipoxygenase, and for their scavenging activity of AOS using the thiobarbituric acid method. 2,3,5-Trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (24, CV-6504) was the most promising derivative since it showed efficient AOS scavenging activity (inhibition of lipid peroxidation in rat brain homogenates: IC₅₀ = 1.8 <*> 10^-6 M) as well as potent, specific, and well-balanced inhibitory effects on both enzymes (inhibitory effect on TXA₂ synthase in human blood, IC₅₀ = 3.3 <*> 10^-7 M; inhibitory effect on 5-lipoxygenase in human blood, IC₅₀ = 3.6 <*> 10^-7 M).In adriamycin-induced proteinuria in a rat model, compound 24 at 10 mg/kg per day (po) suppressed proteinuria by more than 50percent.The proteinuria, however, could not be reduced by single administration of an inhibitor specific for thromboxane A₂ synthase <(E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2, CV-4151)> or for 5-lipoxygenase <2-(12-hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl-1,4-benzoquinone (1, AA-861)>.The proteinuria was also not reduced by administration of an AOS scavenger, 2-O-octadecylascorbic acid (4, CV-3611).Triple function compounds such as compound 24 that specifically inhibit both enzymes as well as scavenge AOS possess a variety of pharmacologically beneficial effects.