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 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.
Rao
Navin L
NL
Johnson and Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
Dunford
Paul J
PJ
Xue
Xiaohua
X
Jiang
Xiaohui
X
Lundeen
Katherine A
KA
Coles
Fawn
F
Riley
Jason P
JP
Williams
Kacy N
KN
Grice
Cheryl A
CA
Edwards
James P
JP
Karlsson
Lars
L
Fourie
Anne M
AM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D001202:Ascitic Fluid / Q000187:drug effects / Q000378:metabolism; D052160:Benzothiazoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004423:Ear / Q000473:pathology; D004487:Edema / Q000473:pathology / Q000517:prevention & control; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D044045:Lipoxins / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D020556:Neutrophil Infiltration / Q000187:drug effects; D010538:Peritonitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052160:Benzothiazoles; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; D010880:Piperidines; D011994:Recombinant Proteins; C040527:lipoxin A4; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017997:Leukotriene C4; C521339:1-(4-(benzothiazol-2-yloxy)benzyl)piperidine-4-carboxylic acid; D004851:Epoxide Hydrolases; C063449:zileuton; C043134:leukotriene A4 hydrolase; D006918:Hydroxyurea