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.
AA-861, a selective inhibitor of 5-lipoxygenase of arachidonic acid, was tested for ability to inhibit leukotriene C4 and leukotriene B4 synthesis in human 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 X 10(-7) M for leukotriene B4 and 1 X 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 1,000 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.
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D016227:Benzoquinones; D001792:Blood Platelets / Q000201:enzymology*; D000001:Calcimycin / Q000494:pharmacology; D004049:Diethylcarbamazine / Q000494:pharmacology; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D009504:Neutrophils / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*; D011720:Pyrazoles / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology*; D013189:SRS-A / Q000096:biosynthesis*
D001095:Arachidonic Acids; D016227:Benzoquinones; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D011809:Quinones; D013189:SRS-A; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D011451:Prostaglandin-Endoperoxide Synthases; D004049:Diethylcarbamazine