Rofecoxib

Rofecoxib is a potent and orally active inhibitor of cyclooxygenase (COX)-2 with IC50 value of 0.34μM [1].

Rofecoxib is an inhibitor of COX-2 and is developed as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. It has been shown to be effective in the treatment of osteoarthritis. Rofecoxib potently inhibits COX-2 in cell-based assays with IC50 values ranging from 18nM to 46nM. In osteosarcoma cells, rofecoxib prevents the production of PGE2 with IC50 value of 26nM. Rofecoxib also shows effective inhibition of recombinant human COX-2 in stably transfected CHO cells with IC50 value of 18nM. Besides that, rofecoxib inhibits the activity of purified human COX-2 with IC50 value of 0.34μM in the in vitro assay with Genapol X-100 [1].

In the carrageenan-induced rat paw edema assay, administration of rofecoxib suppresses the edema response with ID50 value of 1.5mg/kg. And in rats with carrageenan-induced paw hyperalgesia, relieves the hyperalgesia with ID50 value of 1mg/kg [1].

References:
[1] Chan C C, Boyce S, Brideau C, et al. Rofecoxib [Vioxx, MK-0966; 4-(4′-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. Journal of Pharmacology and Experimental Therapeutics, 1999, 290(2): 551-560.

Rofecoxib inhibits retinal neovascularization via down regulation of cyclooxygenase-2 and vascular endothelial growth factor expression.[Pubmed:25472856]

Clin Exp Ophthalmol. 2015 Jul;43(5):458-65.

BACKGROUND: To explore the anti-angiogenesis mechanism of Rofecoxib and determine whether Rofecoxib can be a therapeutic agent for the prevention of retinal neovascularization using a model of retinopathy of prematurity (ROP). METHODS: ROP was induced by exposing mice to 75% oxygen from postnatal day 7 (P7 ) to P12 , then to room air from P12 to P17 . Sixteen mice were in each of the three groups: untreated ROP group as positive control, Rofecoxib-treated ROP group and the normal group (age-matched mice maintained in room air from birth to P17 as negative control). The localized expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) protein and mRNA in retinal blood vessels was assessed using immunohistochemistry, Western blot analysis and reverse transcription polymerase chain reaction. RESULTS: Mice in the Rofecoxib-treated group had a significantly reduced retinal neovascular tufts compared with those in the untreated ROP group. COX-2 and VEGF protein and mRNA expression levels were increased in the untreated ROP group, compared with the normal group. Rofecoxib decreased retinal angiogenesis by inhibiting COX-2 and VEGF expression. The expression levels of VEGF and COX-2 were positively correlated at mRNA and protein levels. CONCLUSIONS: COX-2 and VEGF expressions were both involved in the regulation of angiogenesis and had the same cellular localization. Expression of COX-2 correlated positively with VEGF in retinal neovascularization. Rofecoxib attenuated retinal angiogenesis by inhibiting the expression of COX-2 and VEGF mRNA and protein.

Rofecoxib-Induced Deleterious Effects Escape Detection by Organismal Performance Assays.[Pubmed:28042224]

J Pharm Negat Results. 2016;7(1):4-11.

BACKGROUND: Organismal Performance Assays (OPAs) are a unique toxicity quantification method used to assess the safety of potentially toxic compounds, such as pharmaceuticals. OPAs utilize genetically diverse wild mice (Mus musculus) housed in semi-natural enclosures wherein exposed individuals compete directly with controls for resources. Previously, OPAs have been successful in detecting adverse effects in mice that were exposed to paroxetine. Here, we further test OPAs utility in pharmaceutical safety assessment by testing OPAs with Rofecoxib, a drug with known adverse effects in humans. METHODS: We exposed mice to Rofecoxib (~37.5 mg/kg/day) during gestation and into early adulthood. Exposure ceased when individuals were released into enclosures. Five independent populations were established and Rofecoxib-exposed individuals (n = 58) competed directly with control individuals (n = 58) over 28 weeks. Organismal performance was determined by quantifying reproduction, survival and male competitive ability. RESULTS: In enclosures, Rofecoxib-exposed males had equal reproduction, survival and competitive ability. Rofecoxib-exposed females had equal survival compared to controls but experienced 40% higher reproductive output. CONCLUSIONS: The adverse health effects of Rofecoxib seen in humans escaped detection by OPAs, just as they had during traditional preclinical assays. These results may be explained by the exposure design (in enclosures, all animals were on the control diet), the relatively short duration of exposure, species differences, or because the health benefits of the drug negated the side effects. Similarly to numerous assays used in preclinical trials, OPAs cannot reveal all maladies, despite their demonstrated sensitivity in detecting cryptic toxicity from numerous exposures.

Crystal structure of rofecoxib bound to human cyclooxygenase-2.[Pubmed:27710942]

Acta Crystallogr F Struct Biol Commun. 2016 Oct 1;72(Pt 10):772-776.

Rofecoxib (Vioxx) was one of the first selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) to be approved for use in humans. Within five years after its release to the public, Vioxx was withdrawn from the market owing to the adverse cardiovascular effects of the drug. Despite the widespread knowledge of the development and withdrawal of Vioxx, relatively little is known at the molecular level about how the inhibitor binds to COX-2. Vioxx is unique in that the inhibitor contains a methyl sulfone moiety in place of the sulfonamide moiety found in other coxibs such as celecoxib and valdecoxib. Here, new crystallization conditions were identified that allowed the structural determination of human COX-2 in complex with Vioxx and the structure was subsequently determined to 2.7 A resolution. The crystal structure provides the first atomic level details of the binding of Vioxx to COX-2. As anticipated, Vioxx binds with its methyl sulfone moiety located in the side pocket of the cyclooxygenase channel, providing support for the isoform selectivity of this drug.

Molecular simulation study on concentration effects of rofecoxib with POPC bilayer.[Pubmed:27693948]

J Mol Graph Model. 2016 Nov;70:94-99.

The interactions between Rofecoxib and POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) bilayer were studied using all-atom molecular dynamics simulation method. Four POPC bilayer systems with different number of Rofecoxib molecules were constructed to simulate different drug concentration. The free energy of Rofecoxib passing across pure POPC bilayer has two minima (at z approximately 1.2nm or 1.6nm). As for the high concentration model, the minimum of the free energy profile slightly shifts to the bilayer center. Moreover, the energy change from bulk water to POPC bilayer increases while the central barrier to cross the hydrophobic core of bilayer slightly decreases, suggesting that increasing drug concentration makes it favorable for Rofecoxib to partition into the bilayer and easier to pass across bialyer center. Energy analysis show that the stabilization between the selected Rofecoxib and other pre-inserted Rofecoxib molecule is mainly due to van der Waals interaction energy. The predicted permeability of Rofecoxib in high concentration model slightly weakens as compared with low concentration model.

Rofecoxib is a potent, specific and orally active COX-2 inhibitor, with IC50s of 26 and 18 nM for human COX-2 in human osteosarcoma cells and Chinese hamster ovary cells, with a 1000-fold selectivity for COX-2 over human COX-1 (IC50 > 50 μM in U937 cells and > 15 μM in Chinese hamster ovary cells).

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