PMID- 17371808
OWN - NLM
STAT- MEDLINE
DCOM- 20070730
LR  - 20190108
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 321
IP  - 3
DP  - 2007 Jun
TI  - Anti-inflammatory activity of a potent, selective leukotriene A4 hydrolase 
      inhibitor in comparison with the 5-lipoxygenase inhibitor zileuton.
PG  - 1154-60
AB  - 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.
FAU - Rao, Navin L
AU  - Rao NL
AD  - Johnson and Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield 
      Row, San Diego, CA 92121, USA.
FAU - Dunford, Paul J
AU  - Dunford PJ
FAU - Xue, Xiaohua
AU  - Xue X
FAU - Jiang, Xiaohui
AU  - Jiang X
FAU - Lundeen, Katherine A
AU  - Lundeen KA
FAU - Coles, Fawn
AU  - Coles F
FAU - Riley, Jason P
AU  - Riley JP
FAU - Williams, Kacy N
AU  - Williams KN
FAU - Grice, Cheryl A
AU  - Grice CA
FAU - Edwards, James P
AU  - Edwards JP
FAU - Karlsson, Lars
AU  - Karlsson L
FAU - Fourie, Anne M
AU  - Fourie AM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20070319
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Benzothiazoles)
RN  - 0 (Eicosanoids)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lipoxins)
RN  - 0 (Lipoxygenase Inhibitors)
RN  - 0 (Piperidines)
RN  - 0 (Recombinant Proteins)
RN  - 0 (lipoxin A4)
RN  - 1HGW4DR56D (Leukotriene B4)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - 2CU6TT9V48 (Leukotriene C4)
RN  - 7W7511NPF8 (1-(4-(benzothiazol-2-yloxy)benzyl)piperidine-4-carboxylic acid)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - V1L22WVE2S (zileuton)
RN  - V38765PUZ6 (leukotriene A4 hydrolase)
RN  - X6Q56QN5QC (Hydroxyurea)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/metabolism/*pharmacology
MH  - Arachidonic Acid/pharmacology
MH  - Ascitic Fluid/drug effects/metabolism
MH  - Benzothiazoles/metabolism/*pharmacology/therapeutic use
MH  - Dogs
MH  - Ear/pathology
MH  - Edema/pathology/prevention & control
MH  - Eicosanoids/metabolism
MH  - Enzyme Inhibitors/metabolism/pharmacology
MH  - Epoxide Hydrolases/*antagonists & inhibitors/genetics/metabolism
MH  - Female
MH  - Humans
MH  - Hydroxyurea/*analogs & derivatives/metabolism/pharmacology
MH  - Inflammation/metabolism/pathology/prevention & control
MH  - Leukotriene B4/metabolism
MH  - Leukotriene C4/metabolism
MH  - Lipoxins/metabolism
MH  - *Lipoxygenase Inhibitors
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred Strains
MH  - Neutrophil Infiltration/drug effects
MH  - Peritonitis/metabolism/pathology/prevention & control
MH  - Piperidines/metabolism/*pharmacology/therapeutic use
MH  - Recombinant Proteins/chemistry/metabolism
EDAT- 2007/03/21 09:00
MHDA- 2007/07/31 09:00
CRDT- 2007/03/21 09:00
PHST- 2007/03/21 09:00 [pubmed]
PHST- 2007/07/31 09:00 [medline]
PHST- 2007/03/21 09:00 [entrez]
AID - jpet.106.115436 [pii]
AID - 10.1124/jpet.106.115436 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2007 Jun;321(3):1154-60. doi: 10.1124/jpet.106.115436. Epub 
      2007 Mar 19.