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.