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

Leukotriene A 4 hydrolase (LTA 4 H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B 4 , 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 recombin...

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Published in:The Journal of pharmacology and experimental therapeutics 2007-06, Vol.321 (3), p.1154-1160
Main Authors: Rao, Navin L, Dunford, Paul J, Xue, Xiaohua, Jiang, Xiaohui, Lundeen, Katherine A, Coles, Fawn, Riley, Jason P, Williams, Kacy N, Grice, Cheryl A, Edwards, James P, Karlsson, Lars, Fourie, Anne M
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents, Non-Steroidal - metabolism
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Arachidonic Acid - pharmacology
Ascitic Fluid - drug effects
Ascitic Fluid - metabolism
Benzothiazoles - metabolism
Benzothiazoles - pharmacology
Benzothiazoles - therapeutic use
Dogs
Ear - pathology
Edema - pathology
Edema - prevention & control
Eicosanoids - metabolism
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Epoxide Hydrolases - antagonists & inhibitors
Epoxide Hydrolases - genetics
Epoxide Hydrolases - metabolism
Female
Humans
Hydroxyurea - analogs & derivatives
Hydroxyurea - metabolism
Hydroxyurea - pharmacology
Inflammation - metabolism
Inflammation - pathology
Inflammation - prevention & control
Leukotriene B4 - metabolism
Leukotriene C4 - metabolism
Lipoxins - metabolism
Lipoxygenase Inhibitors
Mice
Mice, Inbred BALB C
Mice, Inbred Strains
Neutrophil Infiltration - drug effects
Peritonitis - metabolism
Peritonitis - pathology
Peritonitis - prevention & control
Piperidines - metabolism
Piperidines - pharmacology
Piperidines - therapeutic use
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
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Summary:Leukotriene A 4 hydrolase (LTA 4 H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B 4 , 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 LTA 4 H (IC 50 , approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA 4 H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB 4 production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED 50 , 1–3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB 4 production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A 4 . The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB 4 , LTC 4 , and LXA 4 production. Although zileuton inhibited LTB 4 production in the peritonitis model more effectively than the LTA 4 H 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 LXA 4 levels in the presence of the LTA 4 H inhibitor. The selective inhibition of LTB 4 production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA 4 , may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB 4 -mediated inflammatory diseases.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.106.115436