Effect of AA‐861, a 5‐Lipoxygenase Inhibitor, on Leukotriene Synthesis in Human Polymorphonuclear Leukocytes and on Cyclooxygenase and 12‐Lipoxygenase Activities in Human Platelets

Abstract

AA-861, a selective inhibitor of 5-lipoxygenase of arachidonic acid, was tested for ability to inhibit the leukotriene C4 and leukotriene B4 synthesis in humans polymorphonuclear leukocytes after calcium ionophore stimulation. AA-861 dose-dependently inhibited leukotriene B4 and leukotriene C4 generation in human polymorphonuclear leukocytes; the concentration required to inhibit generation by 50% (IC50) was 3 .times. 10-7 M for leukotriene B4 and 1 .times. 10-8 M for leukotriene C4. BW-755C inhibited the generation of leukotriene C4 with an IC50 of about 10-5 M, indicating that AA-861 is about 1000 times more potent than BW-755C AA-861 did not affect the activity of either cyclooxygenase or 12-lipoxygenase at a concentration up to 10-5 M in human platelets. AA-861 did not inhibit histamine release from human basophils. These results indicate that AA-861 selectively inhibits 5-lipoxygenase but not cyclooxygenase or 12-lipoxygenase in human specimens.