In vitro effects of E3040, a dual inhibitor of 5-lipoxygenase and thromboxane A(2) synthetase, on eicosanoid production.
In vitro pharmacological profiles of E3040, 6-hydroxy-5, 7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazole were investigated. Against the 5-lipoxygenase activity of rat basophilic leukemia cells, E3040 and zileuton (a 5-lipoxygenase inhibitor) had an IC(50) of 0.23 and 0.93 microM, respectively. Against the thromboxane A(2) synthetase activity of human platelets, E3040 had an IC(50) of 0.01 microM, which was comparable to that of OKY-1581 (sodium (E)-3-[4-(3-pyridylmethyl) phenyl]-2-methylacrylate, a thromboxane A(2) synthetase inhibitor). Against cyclooxygenase activity of sheep seminal vesicles, E3040 showed no inhibition (IC(50), >300 microM). Sulfasalazine and 5-aminosalicylic acid, therapeutic drugs for inflammatory bowel disease, inhibited 5-lipoxygenase activity with an IC(50) of 293 and 970 microM, respectively. Sulfasalazine inhibited thromboxane A(2) synthetase activity with an IC(50) of 20 microM. In rat peritoneal leukocytes, E3040 inhibited leukotriene B(4) and thromboxane B(2) production with an IC(50) of 0.17 and 0.24 microM, respectively. E3040 inhibited leukotriene B(4) production in human neutrophils and thromboxane B(2) production in human platelets (IC(50) of 0.21 and 0.09 microM, respectively). These results indicated that E3040 potently inhibited 5-lipoxygenase and thromboxane A(2) synthetase and blocked leukotriene B(4) and thromboxane B(2) production in rat peritoneal and human blood cells.
Oketani
K
K
Tsukuba Research Laboratories, Eisai Co., Ltd., 1-3, Tokodai-5-chome, Tsukuba, Ibaraki 300-2635, Japan. k-oketani@hhc.eisai.co.jp
Nagakura
N
N
Harada
K
K
Inoue
T
T
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D052160:Benzothiazoles; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D019804:Mesalamine / Q000494:pharmacology; D008689:Methacrylates / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010529:Peritoneal Cavity / Q000166:cytology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012756:Sheep; D012460:Sulfasalazine / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D052160:Benzothiazoles; D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D008689:Methacrylates; D011725:Pyridines; D013844:Thiazoles; C095803:E 3040; D007975:Leukotriene B4; D012460:Sulfasalazine; D019804:Mesalamine; D013929:Thromboxane B2; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; C063449:zileuton; D006918:Hydroxyurea; D007213:Indomethacin