Anti-Inflammatory Activity of a Potent, Selective Leukotriene A4 Hydrolase Inhibitor in Comparison with the 5-Lipoxygenase Inhibitor Zileuton

Publisher Website
Google Scholar
Abstract
Leukotriene A4 hydrolase (LTA4H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B4, which is implicated in a number of inflammatory diseases. We have identified a potent and selective inhibitor of both the epoxide hydrolase and aminopeptidase activities of recombinant human LTA4H (IC50, approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA4H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB4 production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED50, 1–3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB4 production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A4. The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB4, LTC4, and LXA4 production. Although zileuton inhibited LTB4 production in the peritonitis model more effectively than the LTA4H inhibitor, the influx of neutrophils into the peritoneum after 1 and 2 h was significantly higher in zileuton- versus JNJ-26993135-treated animals. This difference may have been mediated by the increased LXA4 levels in the presence of the LTA4H inhibitor. The selective inhibition of LTB4 production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA4, may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB4-mediated inflammatory diseases.