TEPOXALIN - A DUAL CYCLOOXYGENASE 5-LIPOXYGENASE INHIBITOR OF ARACHIDONIC-ACID METABOLISM WITH POTENT ANTIINFLAMMATORY ACTIVITY AND A FAVORABLE GASTROINTESTINAL PROFILE

Tepoxalin hlorophenyl)-N-hydroxy-(4-methoxyphenyl)N-methyl-1 H-pyrazol e-3-propanamide] is a potent inhibitor of sheep seminal vesicle cycloo xygenase (CO) (lC(50) = 4.6 mu M), rat basophilic leukemia cell (RBL-1 ) lysate CO (IC50 = 2.85 mu M) acid CO from intact RBL-1 cells (IC50 = 4.2 mu M). The compound inhibits the production of thromboxane B-2 (T xB(2)) in Ca++ ionophore A-23187-stimulated human peripheral blood leu kocytes (HPBL; IC50 = 0.01 mu M) and human whole blood (IC50 = 0.08 mu M) and is a potent inhibitor of epinephrine-induced human platelet ag gregation (IC50 = 0.045 mu M). Tepoxalin inhibits lipoxygenase (LO) in RBL-1 lysates (IC50 = 0.15 mu M) and intact RBL-1 cells (IC50 = 1.7 m u M) and inhibits the generation of leukotriene B-4 (LTB(4)) in calciu m ionophore A-23187-stimulated HPBL (IC50 = 0.07 mu M) and human whole blood (IC50 = 1.57 mu M). Human platelet 12-LO (IC50 = 3.0 mu M) is i nhibited, but 15-LO is only weakly so (IC50 = 157 mu M), In vivo, tepo xalin, administered orally, demonstrated potent anti-inflammatory acti vity in the established adjuvant arthritic rat (ED(50) = 3.5 mg/kg) an d potent analgesic activity in the acetic acid abdominal construction assay in mice (ED(50) = 0.45 mg/kg). In an ex vivo whole blood eicosan oid production assay, tepoxalin produces a dose-related inhibition of prostaglandin (PG) and LT production in dogs (PGF(2 alpha) - ED(50) = 0.015 mg/kg; LTB(4) - ED(50) = 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 therape utic 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 immu noinflammatory disease states where excessive PC and LT production has been implicated and may offer a significant alternative to nonsteroid al and corticosteroidal anti-inflammatory therapy.