Contrasting effects of two arachidonate 5-lipoxygenase inhibitors on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a induced human neutrophil superoxide generation.

SC-45662 and SC-41661A, selective arachidonate 5-lipoxygenase (5-LO) inhibitors, had markedly different effects on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a (C5a) induced superoxide release from human neutrophils (PMNs). SC-45662 inhibited superoxide generation induced by fMLP and C5a with IC50 values of 12 and 5 microM, respectively. Furthermore, SC-45662 was capable of inhibiting fMLP and C5a induced superoxide release in PMNs primed with bacterial lipopolysaccharide, tumor necrosis factor-alpha and other priming agents. SC-41661A, a compound from the same chemical series as SC-45662, did not inhibit or induce superoxide generation, but instead primed PMNs for fMLP and C5a induced superoxide generation. The induced superoxide release was concentration dependently enhanced 2 to 4-fold at 5-50 microM. Superoxide release induced by phorbol myristate acetate or serum-activated zymosan was unaffected by either SC-45662 or SC-41661A. The regulation of superoxide generation by these compounds, both of which have the identical oxidation-reduction pharmacophore, was clearly independent of their effects on 5-LO activity. Furthermore, the mechanism by which SC-45662 and SC-41661A alter superoxide generation did not appear to depend on inhibition of xanthine oxidase, catalase or superoxide dismutase. These new compounds provide effective tools for further investigation of the relationship of these two biochemical oxidative systems.

Multiple actions of the leukotriene B4 receptor antagonist SC-41930.

7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl-2H-1-benzopyran-2-carboxylic acid (SC-41930), a leukotriene B4 (LTB4) receptor antagonist with anti-inflammatory activity in animal models of colitis, was evaluated for effects on superoxide, LTB4 and prostaglandin E2 production. SC-41930 inhibited human neutrophil (PMN) superoxide generation maximally stimulated by f-Met-Leu-Phe (IC50 4 microM) and C5a (IC50 approximately 12 microM). Moreover, postreceptor stimulation of superoxide production by NaF (a G protein activator), but not by phorbol myristate acetate, was significantly inhibited by SC-41930, indicating that SC-41930 may act via attenuation of a G protein-mediated signal transduction. SC-41930 also inhibited A23187-stimulated LTB4 production (IC50 5.3 microM) in human PMN as well as LTB4 (IC50 2.1 microM) and prostaglandin E2 (IC50 2.9 microM) production in HL-60 cells. When coinjected intradermally (400 micrograms/site), SC-41930 inhibited A23187-stimulated increases in LTB4 levels in guinea pig skin. SC-41930 inhibited human synovial phospholipase A2 (IC50 72 microM), A23187-stimulated 5-hydroxy-eicosatetranoic acid production in human PMN (IC50 8.5 microM), and rat peritoneal leukotriene A4 hydrolase (IC50 20 microM), but not ram seminal vesical cyclooxygenase. The results suggest that the anti-inflammatory activity of SC-41930 could be attributed to postreceptor inhibition of inflammatory mediator production by PMN and other cells in addition to antagonism of PMN LTB4 receptors.