In vitro effects of E3040, a dual inhibitor of 5-lipoxygenase and thromboxane A2 synthetase, on eicosanoid production

Abstract 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 μM, respectively. Against the thromboxane A 2 synthetase activity of human platelets, E3040 had an IC 50 of 0.01 μM, 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 μM). Sulfasalazine and 5-aminosalicylic acid, therapeutic drugs for inflammatory bowel disease, inhibited 5-lipoxygenase activity with an IC 50 of 293 and 970 μM, respectively. Sulfasalazine inhibited thromboxane A 2 synthetase activity with an IC 50 of 20 μM. In rat peritoneal leukocytes, E3040 inhibited leukotriene B 4 and thromboxane B 2 production with an IC 50 of 0.17 and 0.24 μM, 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 μM, 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.