Tepoxalin: a dual cyclooxygenase/5-lipoxygenase inhibitor of arachidonic acid metabolism with potent anti-inflammatory activity and a favorable gastrointestinal profile.
Tepoxalin [5-(4-chlorophenyl)-N-hydroxy-(4-methoxyphenyl)-N-methyl-1H- pyrazole-3-propanamide] is a potent inhibitor of sheep seminal vesicle cyclooxygenase (CO) (IC50 = 4.6 microM), rat basophilic leukemia cell (RBL-1) lysate CO (IC50 = 2.85 microM) and CO from intact RBL-1 cells (IC50 = 4.2 microM). The compound inhibits the production of thromboxane B2 (TxB2) in Ca++ ionophore A-23187-stimulated human peripheral blood leukocytes (HPBL; IC50 = 0.01 microM) and human whole blood (IC50 = 0.08 microM) and is a potent inhibitor of epinephrine-induced human platelet aggregation (IC50 = 0.045 microM). Tepoxalin inhibits lipoxygenase (LO) in RBL-1 lysates (IC50 = 0.15 microM) and intact RBL-1 cells (IC50 = 1.7 microM) and inhibits the generation of leukotriene B4 (LTB4) in calcium ionophore A-23187-stimulated HPBL (IC50 = 0.07 microM) and human whole blood (IC50 = 1.57 microM). Human platelet 12-LO (IC50 = 3.0 microM) is inhibited, but 15-LO is only weakly so (IC50 = 157 microM). In vivo, tepoxalin, administered orally, demonstrated potent anti-inflammatory activity in the established adjuvant arthritic rat (ED50 = 3.5 mg/kg) and potent analgesic activity in the acetic acid abdominal construction assay in mice (ED50 = 0.45 mg/kg). In an ex vivo whole blood eicosanoid production assay, tepoxalin produces a dose-related inhibition of prostaglandin (PG) and LT production in dogs (PGF2 alpha - ED50 = 0.015 mg/kg; LTB4 - ED50 = 2.37 mg/kg) and adjuvant arthritic rats following oral administration. In adjuvant arthritic rats, tepoxalin is devoid of ulcerogenic activity within its anti-inflammatory therapeutic range (1-33 mg/kg p.o.) and does not exhibit ulcerogenic activity in normal rats at doses lower than 100 mg/kg (UD50 = 173 mg/kg p.o.). Tepoxalin represents a new class of anti-inflammatory drugs which may exhibit less gastrointestinal toxicity and may be efficacious in immunoinflammatory disease states where excessive PG and LT production has been implicated and may offer a significant alternative to nonsteroidal and corticosteroidal anti-inflammatory therapy.
Argentieri
D C
DC
Research Laboratories, R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey.
Ritchie
D M
DM
Ferro
M P
MP
Kirchner
T
T
Wachter
M P
MP
Anderson
D W
DW
Rosenthale
M E
ME
Capetola
R J
RJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004285:Dogs; D015777:Eicosanoids / Q000096:biosynthesis; D005260:Female; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D012756:Sheep; D013276:Stomach Ulcer / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D016718:Arachidonic Acid; C073135:tepoxalin