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

J Med Chem. 1991 Jan;34(1):267-76. doi: 10.1021/jm00105a042.

Abstract

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 x 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 x 10(-7) M; inhibitory effect on 5-lipoxygenase in human blood, IC50 = 3.6 x 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 50%. 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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzoquinones / chemical synthesis*
  • Benzoquinones / chemistry
  • Benzoquinones / pharmacology
  • Binding Sites
  • Blood Platelets / enzymology
  • Cell Line
  • Free Radical Scavengers*
  • Horses
  • Indicators and Reagents
  • Leukemia, Basophilic, Acute / enzymology
  • Lipoxygenase Inhibitors*
  • Male
  • Microsomes / enzymology
  • Molecular Structure
  • Rats
  • Rats, Inbred Strains
  • Structure-Activity Relationship
  • Thromboxane-A Synthase / antagonists & inhibitors*
  • Thromboxane-A Synthase / blood

Substances

  • Benzoquinones
  • Free Radical Scavengers
  • Indicators and Reagents
  • Lipoxygenase Inhibitors
  • Thromboxane-A Synthase