4-(4-methanesulfonylphenyl)-3-phenyl-2,5-dihydrofuran-2-one

• ChemBase ID: 415
• Molecular Formular: C17H14O4S
• Molecular Mass: 314.35566
• Monoisotopic Mass: 314.06127993
• SMILES: S(=O)(=O)(c1ccc(C2=C(c3ccccc3)C(=O)OC2)cc1)C
• Canonical SMILES: O=C1OCC(=C1c1ccccc1)c1ccc(cc1)S(=O)(=O)C
• InChI: InChI=1S/C17H14O4S/c1-22(19,20)14-9-7-12(8-10-14)15-11-21-17(18)16(15)13-5-3-2-4-6-13/h2-10H,11H2,1H3
• InChIKey: RZJQGNCSTQAWON-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-(4-methanesulfonylphenyl)-3-phenyl-2,5-dihydrofuran-2-one
• IUPAC Traditional name: rofecoxib; 4-(4-methanesulfonylphenyl)-3-phenyl-2,5-dihydrofuran-2-one
• Brand Name: Vioxx
• Synonyms: MK 966; MK 996; rofecoxib; Rofecoxib; 4-[4-(Methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone; 3-(4-Methanesulfonylphenyl)-2-phenyl-2-buten-4-olide; 3-Phenyl-4-[4-(Methylsulfonyl)phenyl]-2(5H)-furanone; MK 0966; Rhuma-cure; Vioxx; Rofecoxib (Vioxx); Vioxx; Ceoxx; Ceeoxx; Rofecoxib

Database IDs

• CAS Number: 162011-90-7; N/A
• PubChem SID: 160963878; 46504787
• PubChem CID: 5090

CALCULATED PROPERTIES

JChem

• Acid pKa: 14.839777
• H Acceptors: 3
• H Donor: 0
• LogD (pH = 5.5): 2.5609105
• LogD (pH = 7.4): 2.5609105
• Log P: 2.5609105
• Molar Refractivity: 84.0801 cm^3
• Polarizability: 33.193634 Å^3
• Polar Surface Area: 60.44 Å^2
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.32
• LOG S: -4.47
• Solubility (Water): 1.06e-02 g/l

PROPERTIES

Physical Property

• Solubility: Chloroform; Dimethyl formamide; DMSO; Insoluble
• Apperance: Off-White Solid
• Melting Point: 207-209°C
• Hydrophobicity(logP): 3.2

Safety Information

• Storage Condition: Refrigerator

Pharmacology Properties

• Target: COX
• Mechanism of Action: Cyclooxygenase-2 inhibitor

Product Information

• Salt Data: Free Base
• Application(s): Nonsteroidal anti-inflammatory drug (NSAID)

DETAILS

DrugBank - DB00533

• Drug Groups: withdrawn; investigational
• Description: On September 30, 2004, Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use.
• Indication: For the treatment of osteoarthritis, rheumatoid arthritis, acute pain in adults, and primary dysmenorrhea, as well as acute treatment of migraine attacks with or without auras.
• Pharmacology: Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Unlike celecoxib, rofecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. Like other NSAIDs, rofecoxib exhibits anti-inflammatory, analgesic, and antipyretic activity. NSAIDs appear to inhibit prostaglandin synthesis via the inhibition of cyclooxygenase (COX), which are responsible for catalyzing the formation of prostaglandins in the arachidonic acid pathyway. There are at least two isoenzymes, COX-1 and COX-2, that have been identified. Although the exact mechanisms have not been clearly established, NSAIDs exert their anti-inflammatory, analgesic, and antipyretic primarily through the inhibition of COX-2. The inhibition of COX-1 is principally responsible for the negative effects on the GI mucosa. As rofecoxib is selective for COX-2, it may be potentially associated with a decreased risk of certain adverse events, but more data is needed to fully evaulate the drug.
• Toxicity: No overdoses of rofecoxib were reported during clinical trials. Administration of single doses of rofecoxib 1000 mg to 6 healthy volunteers and multiple doses of 250 mg/day for 14 days to 75 healthy volunteers did not result in serious toxicity.
• Affected Organisms: Humans and other mammals
• Biotransformation: Hepatic. Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. The principal metabolic products are the cis-dihydro and trans-dihydro derivatives of rofecoxib, which account for nearly 56% of recovered radioactivity in the urine. An additional 8.8% of the dose was recovered as the glucuronide of the hydroxy derivative, a product of oxidative metabolism. The biotransformation of rofecoxib and this metabolite is reversible in humans to a limited extent (< 5%). These metabolites are inactive as COX-1 or COX-2 inhibitors. Cytochrome P450 plays a minor role in metabolism of rofecoxib.
• Absorption: The mean oral bioavailability of rofecoxib at therapeutically recommended doses of 12.5, 25, and 50 mg is approximately 93%.
• Half Life: 17 hours
• Protein Binding: 87%
• References: Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23;343(21):1520-8, 2 p following 1528. [Pubmed] ; Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005 Mar 17;352(11):1092-102. Epub 2005 Feb 15. [Pubmed] ; Curfman GD, Morrissey S, Drazen JM: Expression of concern reaffirmed. N Engl J Med. 2006 Mar 16;354(11):1193. Epub 2006 Feb 22. [Pubmed] ; Fitzgerald GA: Coxibs and cardiovascular disease. N Engl J Med. 2004 Oct 21;351(17):1709-11. Epub 2004 Oct 6. [Pubmed] ; Karha J, Topol EJ: The sad story of Vioxx, and what we should learn from it. Cleve Clin J Med. 2004 Dec;71(12):933-4, 936, 938-9. [Pubmed] ; Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, Iverson ER, Demets DL: Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet. 2008 Nov 15;372(9651):1756-64. Epub 2008 Oct 14. [Pubmed] ; Matheson AJ, Figgitt DP: Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Drugs. 2001;61(6):833-65. [Pubmed] ; Hillson JL, Furst DE: Rofecoxib. Expert Opin Pharmacother. 2000 Jul;1(5):1053-66. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Toronto Research Chemicals - V670000

A selective cyclooxygenase-2 (COX-2) inhibitor. Use as an anti-inflammatory, analgesic.

REFERENCES

• Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23;343(21):1520-8, 2 p following 1528. Pubmed
• Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005 Mar 17;352(11):1092-102. Epub 2005 Feb 15. Pubmed
• Curfman GD, Morrissey S, Drazen JM: Expression of concern reaffirmed. N Engl J Med. 2006 Mar 16;354(11):1193. Epub 2006 Feb 22. Pubmed
• Fitzgerald GA: Coxibs and cardiovascular disease. N Engl J Med. 2004 Oct 21;351(17):1709-11. Epub 2004 Oct 6. Pubmed
• Karha J, Topol EJ: The sad story of Vioxx, and what we should learn from it. Cleve Clin J Med. 2004 Dec;71(12):933-4, 936, 938-9. Pubmed
• Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, Iverson ER, Demets DL: Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet. 2008 Nov 15;372(9651):1756-64. Epub 2008 Oct 14. Pubmed
• Matheson AJ, Figgitt DP: Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Drugs. 2001;61(6):833-65. Pubmed
• Hillson JL, Furst DE: Rofecoxib. Expert Opin Pharmacother. 2000 Jul;1(5):1053-66. Pubmed
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