Valdecoxib

Valdecoxib is a potent and selective inhibitor of cyclooxygenase-2 (COX-2) with IC50 value of 5nM [1].

Valdecoxib is developed for the management of pain and inflammation. Valdecoxib and its intravenous prodrug parecoxib exert significant opioid-sparing effects after dental, gynecologic, orthopedic and other noncardiac surgical procedures. In the cellular assay, valdecoxib shows inhibitory activity on human recombinant COX-2 with IC50 value of 5nM. It shows no significant effect on COX-1 with IC50 value of 140μM. In the ex vivo assay using human whole blood, valdecoxib prevents PGE2 production with IC50 value of 0.89μM. Moreover, oral administration of valdecoxib exerts chronic anti-inflammatory activity with ED50 value of 0.032 mg/kg/day in the rat adjuvant arthritis model. In addition, valdecoxib is reported to have cardiovascular risk adverse effect in patients undergoing CABG [1, 2].

References:
[1] Talley J J, Brown D L, Carter J S, et al. 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. Journal of medicinal chemistry, 2000, 43(5): 775-777.
[2] Nussmeier N A, Whelton A A, Brown M T, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. New England Journal of Medicine, 2005, 352(11): 1081-1091.

Simultaneous determination of parecoxib sodium and its active metabolite valdecoxib in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study after intravenous and intramuscular administration.[Pubmed:27107851]

J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Jun 1;1022:220-229.

In this study, we developed and validated a new, rapid, specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to simultaneously determine parecoxib sodium (PX) and its active metabolite, Valdecoxib (VX), in rat plasma. Plasma samples were prepared by plasma protein precipitation combined with a liquid-liquid extraction method. The separation was carried out on a Kinetex C18 column (2.1mmx50mm, 2.6mum) with a gradient elution using methanol (A) and a 2mM ammonium acetate aqueous solution (B). The analysis was performed in less than 3min with a flow rate of 0.2mL/min. Ketoprofen was used as an internal standard (IS). Mass spectrometric detection was conducted with a triple quadrupole detector equipped with electrospray ionization in the negative ion mode (ESI(-)) using multiple reaction monitoring (MRM). The calibration curves were linear over the concentration ranges of 5-4000ng/mL for PX and 5-2000ng/mL for VX with all correlation coefficients greater than 0.998. The intra- and inter-day relative standard deviations (RSD) for both analytes were within 15% and the accuracy was within 85-115% at all quality control levels. The mean extraction recoveries for all analytes obtained from three concentrations of QC plasma samples were more than 89.0% efficient. Selectivity, matrix effect, dilution integrity and stability were also validated. The method was successfully used to investigate the pharmacokinetics of PX and VX in rat plasma after intravenous and intramuscular administration of PX.

Valdecoxib Recovers the Lipid Composition, Order and Dynamics in Colon Cancer Cell Lines Independent of COX-2 Expression: An ATR-FTIR Spectroscopy Study.[Pubmed:27354402]

Appl Spectrosc. 2017 Jan;71(1):105-117.

Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenases (COXs). Aberrant expression of the inducible isoform COX-2 plays a significant role in colon cancer initiation and progression. In this study, we have hypothesized that COX-2 specific inhibitors such as Valdecoxib (VLX), being highly hydrophobic, may alter biophysical properties of cellular lipids. In this study, COX-2 expressing (HT29) and COX-2 non-expressing (SW620) colon cancer cell lines were treated with VLX and examined using attenuated total reflection infrared spectroscopy. The results revealed that VLX treatment decreased lipid fluidity in the cells irrespective of COX-2 expression status and affected order parameters of the lipids in both cell lines. Cluster analysis also indicated that the spectral differences between the two cell lines are profound and could be successfully differentiated. Valdecoxib treatment could enhance the composition, order and dynamics of the lipids of colon cancer cells independently of its COX-2 inhibitory mechanism. Valdecoxib has therapeutic effects upon colon cancer, therefore it can be used as an adjuvant and/or chemopreventive agent for colon cancer.

The pharmacokinetics and in vitro/ex vivo cyclooxygenase selectivity of parecoxib and its active metabolite valdecoxib in cats.[Pubmed:25135338]

Vet J. 2014 Oct;202(1):37-42.

Parecoxib (PX) is an injectable prodrug of Valdecoxib (VX, which is a selective cyclo-oxyganase-2 (COX-2)) inhibitor licensed for humans. The aim of the present study was to evaluate pharmacokinetics and in vitro/ex vivo cyclooxygenase selectivity of PX and VX in cats. In a whole blood in vitro study, PX did not affect either COX enzymes whereas VX revealed a COX-2 selective inhibitory effect in feline whole blood. The IC50 values of VX for COX-2 and COX-1 were 0.45 and 38.6 microM, respectively. Six male cats were treated with 2.5 mg/kg of PX by intramuscular injection. PX was rapidly converted to VX with a relatively short half-life of 0.4 h. VX achieved peak plasma concentration (2.79 +/- 1.59 microg/mL) at 7 h following PX injection. The mean residence times for PX and VX were 0.43 +/- 0.15 and 5.94 +/- 0.88 h, respectively. In the ex vivo study, PX showed a COX-2 inhibition rate of about 70% in samples taken at 1, 2, 4 and 10 h after injection, with a significant difference compared to the control. In contrast, COX-1 was slightly inhibited, ranging from 0.7% to 9.7% of the control inhibition rate without any significant difference for 24 h after PX administration. The preliminary findings of the present research appear promising and encourage further studies to investigate whether PX can be successfully used in feline medicine.

Oxime-mediated facile access to 5-methylisoxazoles and applications in the synthesis of valdecoxib and oxacillin.[Pubmed:25255195]

Org Lett. 2014 Oct 17;16(20):5266-8.

A palladium-catalyzed efficient synthesis of 5-methylisoxazoles via oxime-mediated functionalization of unactivated olefins is described. The reaction affords a variety of 5-methylisoxazoles in moderate to good yields. To further demonstrate the utility of the method, the rapid synthesis of Valdecoxib and oxacillin is reported.

Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity.[Pubmed:15494548]

J Pharmacol Exp Ther. 2005 Mar;312(3):1206-12.

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 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM 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) approximately 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). 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) = 0.24 microM; COX-1 IC(50) = 21.9 microM). 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) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 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.

A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors.[Pubmed:11463341]

Biochem J. 2001 Aug 1;357(Pt 3):709-18.

Cyclo-oxygenase (COX) enzymes are the targets for non-steroidal anti-inflammatory drugs (NSAIDs). These drugs demonstrate a variety of inhibitory mechanisms, which include simple competitive, as well as slow binding and irreversible inhibition. In general, most NSAIDs inhibit COX-1 and -2 by similar mechanisms. A unique class of diarylheterocyclic inhibitors has been developed that is highly selective for COX-2 by virtue of distinct inhibitory mechanisms for each isoenzyme. Several of these inhibitors, with varying selectivity, have been utilized to probe the mechanisms of COX inhibition. Results from analysis of both steady-state and time-dependent inhibition were compared. A generalized mechanism for inhibition, consisting of three sequential reversible steps, can account for the various types of kinetic behaviour observed with these inhibitors.

Valdecoxib is a highly potent and selective inhibitor of COX-2, with IC50s of 5 nM and 140 μM for COX-2 and COX-1, respeceively. Valdecoxib can be used in the research of arthritis and pain.

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