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-(meth ylamino)-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,,, of 0.23 and 0.93 muM. respective ly. Against the thromboxane A, synthetase activity of human platelets, E304 0 had an IC50 of 0.01 muM. which was comparable to that of OKY-1581 (sodium (E)-3-[4-(3-pyridylmethyl) phenyl]-3-methylacrylate, a thromboxane A, synt hetase inhibitor). Against cyclooxygenase activity of sheep seminal vesicle s, E3040 showed no inhibition (IC50, > 300 muM). Sulfasalazine and 5-aminos alicylic acid, therapeutic drugs for inflammatory bowel disease, inhibited 5-lipoxygenase activity with an IC50, of 293 and 970 muM, respectively. Sul fasalazine inhibited thromboxane A(2) synthetase activity with an IC50, of 20 muM. In rat peritoneal leukocytes, E3040 inhibited leukouiene B-4 and th romboxane B-2 production with an IC50 of 0.17 and 0.24 muM, respectively. E 3040 inhibited leukotriene B-4 production in human neutrophils and thrombox ane B-2 production in human platelets (IC50 of 0.21 and 0.09 muM, respectiv ely). These results indicated that E3040 potently inhibited 5-lipoxygenase and thromboxane Az synthetase and blocked leukotriene B-4 and thromboxane B -2 production in rat peritoneal and human blood cells. (C) 2001 Elsevier Sc ience B.V. All rights reserved.