Valdecoxib: Assessment of Cyclooxygenase-2 Potency and Selectivity

Abstract

The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human COX-1 and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant COX-2, with an IC 50 of 0.005 M; this compares with IC 50 values of 0.05 M for celecoxib, 0.5 M for rofecoxib, and 5 M for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t 1/2 ϳ98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC 50 ϭ 150 M). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC 50 ϭ 0.24 M; COX-1 IC 50 ϭ 21.9 M). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED 50 ϭ 0.06 mg/kg; paw edema ED 50 ϭ 5.9 mg/kg; adjuvant arthritis ED 50 ϭ 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans.

Pre-existent Asymmetry in the Human Cyclooxygenase-2 Sequence Homodimer

“…In contrast, mutations of Arg-120 in E cat do not have major effects on time-dependent inhibition by either flurbiprofen or naproxen. Consistent with previous reports (31,33,46,48,49,64), time-dependent inhibition by celecoxib and related compounds is insensitive to mutations of Arg-120 in either E allo or E cat . Time-dependent inhibition by indomethacin was partially attenuated by mutations of Arg-120 in E cat and unaffected by mutations of Arg-120 in E allo .…”

“…6A). Celecoxib binding does not involve an important interaction with Arg-120 (48,49), so this result was not surprising. Time-dependent inhibition by indomethacin was relatively unaffected by substitutions of Arg-120 in E allo but was attenuated by substitutions of Arg-120 in E cat .…”

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

“…Compound 10a was sufficiently absorbed, its absolute bioavailability being 42% (F%). The clearance after iv treatment (∼2 L/h) was higher than the rate of blood flow in the rat (0.8 L/h), 32 thus indicating that 10a is a highclearance drug. The volume of distribution after iv treatment (∼5.6 L) was higher than the total volume of body fluid in the rat (0.17 L), 32 indicating extensive distribution of 10a into extravascular compartments.…”

“…The discrepancy between these results and those found in the cell-based assay could be due to a different inhibitor sensitivity exhibited by the mouse and human COX isozymes, as already reported for other anti-inflammatory compounds. 10 As a matter of the fact, such a dramatic loss in COX inhibitory potency and a drop in selectivity under the HWB assay conditions are common to other selective COX-2 inhibitors, such as valdecoxib, 31,32 etoricoxib, 31,32 lumiracoxib, 33 and rofecoxib, 34,35 as well as tNSAIDs such as nimesulide 16,31 and meloxicam. 36,37 It should be pointed out that, according to the test, 10a, 10c, and 11c exhibited an affinity for COX-2 5-10-fold higher than that for COX-1, which should translate clinically into an acceptable GI safety, and allowing for a sufficient prostacyclin generation that should mitigate the CV effects showed by overly selective COX-2 inhibitors, as previously discussed.…”

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

“…Thus, a dramatic loss in COX inhibition potency and drop in selectivity when using the human whole blood assays are shared with other selective COX-2 inhibitors such as valdecoxib [33,34], etoricoxib [33,34], lumiracoxib [35] and rofecoxib [36,37] as well as (t)NSAID such as nimesulide [33,38] and meloxicam [39,40].…”