Etoricoxib (MK-0663): Preclinical profile and comparison with other agentsthat selectively inhibit cyclooxygenase-2

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 s ensitive COX-1 enzyme assays at low substrate concentration. Etoricoxib sel ectively inhibited COX-2 in human whole blood assays in vitro, with an IC50 value of 1.1 +/- 0.1 muM for COX-2 (LPS-induced prostaglandin E-2 synthesi s), compared with an IC50 value of 116 +/- 8 muM for COX-1 (serum thromboxa ne B-2 generation after clotting of the blood). Using the ratio of IC50 val ues (COX-1/COX-2), the selectivity ratio for the inhibition of COX-2 by eto ricoxib 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, nimesulid e, etodolac, and meloxicam, respectively. Etoricoxib did not inhibit platel et or human recombinant COX-1 under most assay conditions (IC50 > 100 muM). In a highly sensitive assay for COX-1 with U937 microsomes where the arach idonic acid concentration was lowered to 0.1 muM, IC50 values of 12, 2, 0.2 5, and 0.05 muM were obtained for etoricoxib, rofecoxib, valdecoxib, and ce lecoxib, respectively. These differences in potency were in agreement with the dissociation constants (K-i) for binding to COX-1 as estimated from an assay based on the ability of the compounds to delay the time-dependent inh ibition by indomethacin. Etoricoxib was a potent inhibitor in models of car rageenan-induced paw edema (ID50 = 0.64 mg/kg), carrageenan-induced paw hyp eralgesia (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% withi n 2 h of administration at a dose of 3 mg/kg and showed no effect in a feca l Cr-51 excretion model of gastropathy at 100 mg/kg/day for 5 days, in cont rast to lower doses of diclofenac or naproxen. In summary, etoricoxib repre sents a novel agent that selectively inhibits COX-2 with 106-fold selectivi ty in human whole blood assays in vitro and with the lowest potency of inhi bition of COX-1 compared with other reported selective agents.