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Vol. 296, Issue 2, 558-566, February 2001
Departments of Pharmacology, Biochemistry, and Molecular Biology
(D.R., M.D.P., C.B., S.C., D.E., J.-P.F., R.G., G.G., J.G., J.M., M.O.,
E.W., L.X., I.W.R., M.G., A.W.F., C.-C.C.) and Medicinal Chemistry
(D.D., R.W.F., Y.G., P.P., R.Z., R.N.Y.), Merck Frosst Centre for
Therapeutic Research, Kirkland, Quebec, Canada; Department of
Pharmacology, Merck Research Laboratories, Harlow, United Kingdom
(S.B.); and Department of Comparative Medicine, Merck Research
Laboratories, Rahway, New Jersey (D.V.)
We report here the preclinical profile of etoricoxib (MK-0663)
[5-chloro-2-(6-methylpyridin-3-yl)-3-(4-methylsulfonylphenyl) pyridine],
a novel orally active agent that selectively inhibits cyclooxygenase-2
(COX-2), that has been developed for high selectivity in vitro using
whole blood assays and sensitive COX-1 enzyme assays at low substrate
concentration. Etoricoxib selectively inhibited COX-2 in human whole
blood assays in vitro, with an IC50 value of 1.1 ± 0.1 µM for COX-2 (LPS-induced prostaglandin E2
synthesis), compared with an IC50 value of 116 ± 8 µM for COX-1 (serum thromboxane B2 generation after
clotting of the blood). Using the ratio of IC50 values
(COX-1/COX-2), the selectivity ratio for the inhibition of COX-2 by
etoricoxib in the human whole blood assay was 106, compared with values
of 35, 30, 7.6, 7.3, 2.4, and 2.0 for rofecoxib, valdecoxib, celecoxib,
nimesulide, etodolac, and meloxicam, respectively. Etoricoxib did not
inhibit platelet or human recombinant COX-1 under most assay conditions
(IC50 > 100 µM). In a highly sensitive assay for
COX-1 with U937 microsomes where the arachidonic acid concentration was
lowered to 0.1 µM, IC50 values of 12, 2, 0.25, and 0.05 µM were obtained for etoricoxib, rofecoxib, valdecoxib, and
celecoxib, respectively. These differences in potency were in agreement
with the dissociation constants (Ki) for
binding to COX-1 as estimated from an assay based on the ability of the compounds to delay the time-dependent inhibition by indomethacin. Etoricoxib was a potent inhibitor in models of carrageenan-induced paw
edema (ID50 = 0.64 mg/kg), carrageenan-induced paw
hyperalgesia (ID50 = 0.34 mg/kg), LPS-induced pyresis
(ID50 = 0.88 mg/kg), and adjuvant-induced arthritis
(ID50 = 0.6 mg/kg/day) in rats, without effects on
gastrointestinal permeability up to a dose of 200 mg/kg/day for 10 days. In squirrel monkeys, etoricoxib reversed LPS-induced pyresis by
81% within 2 h of administration at a dose of 3 mg/kg and showed
no effect in a fecal 51Cr excretion model of gastropathy at
100 mg/kg/day for 5 days, in contrast to lower doses of diclofenac or
naproxen. In summary, etoricoxib represents a novel agent that
selectively inhibits COX-2 with 106-fold selectivity in human whole
blood assays in vitro and with the lowest potency of inhibition of
COX-1 compared with other reported selective agents.
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