ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor with potent anti-inflammatory activity in an arachidonic acid-induced ear inflammation model.
OBJECTIVE
To investigate the effect of ER-34122, a novel pyrazole derivative, on 5-lipoxygenase (LOX) and cyclooxygenase (COX) metabolite production in vitro, ex vivo and in vivo.


METHODS
In vitro, lysate of rat basophilic leukemia cells, the microsome fraction of sheep seminal vesicles, human polymorphonuclear leukocytes, human synovial cells, and human monocytes. Ex vivo and in vivo, male Balb/c mice or SD rats.


METHODS
In ex vivo study, ER-34122 (0.03-1 mg/kg) was orally administered 1 h before withdrawal of blood samples. In carrageenin-induced paw edema, ER-34122 (3-100 mg/kg) and indomethacin (1-10mg/kg) were orally administered 1 h before carrageenin injection. In arachidonic acid-induced ear inflammation, ER-34122 (0.3-10mg/kg), zileuton (10-100mg/kg) and indomethacin (0.3-3mg/kg) were orally administered 1 h before arachidonic acid application.


METHODS
5-Hydroxyeicosatetraenoic acid and other eicosanoids were determined by using an HPLC method and enzyme immunoassay, respectively. Rat hind paw edema and mouse ear edema were assessed by measuring paw volume and ear thickness, respectively. Myeloperoxidase (MPO) activity and eicosanoid content of the ear tissue were also determined.


RESULTS
ER-34122 inhibited both LOX and COX product generation in vitro, and ex vivo. ER-34122 and indomethacin inhibited carrageenin-induced paw edema formation. In the arachidonic acid-induced ear inflammation, ER-34122 inhibited inflammatory responses (edema formation and MPO accumulation) as well as eicosanoids (LTB4, LTC4 and PGE2) generation. A representative LOX inhibitor, zileuton, also inhibited these inflammatory responses, while a COX inhibitor, indomethacin, did not suppress them though it completely inhibited PGE2 generation.


CONCLUSIONS
The anti-inflammatory characteristics of ER-34122 are considered to be superior to those of COX inhibitors such as indomethacin, because in addition to its inhibitory activity on the COX pathway, ER-34122 inhibits LOX products generation, as revealed by the inhibition of edema formation or polymorphonuclear leukocyte infiltration in the arachidonic acid-induced ear inflammation model.
Horizoe
T
T
Eisai Co., Ltd., Tsukuba Research Laboratories for Drug Discovery, Biology Unit 5, Ibaraki, Japan.
Nagakura
N
N
Chiba
K
K
Shirota
H
H
Shinoda
M
M
Kobayashi
N
N
Numata
H
H
Okamoto
Y
Y
Kobayashi
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016718:Arachidonic Acid; D001549:Benzamides / Q000627:therapeutic use*; D002351:Carrageenan; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000096:biosynthesis; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use; D007975:Leukotriene B4 / Q000096:biosynthesis; D017997:Leukotriene C4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010031:Otitis / Q000139:chemically induced / Q000188:drug therapy*; D009195:Peroxidase / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D012756:Sheep; D014407:Tumor Cells, Cultured
C116824:5-((1,5-bis(4-methoxyphenyl)pyrazol-3-yl)dimethoxymethyl)-2-chlorobenzamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017997:Leukotriene C4; D002351:Carrageenan; D009195:Peroxidase; D015232:Dinoprostone; D007213:Indomethacin