COX-2

Nomenclature: COX-2

Family: Eicosanoid turnover

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 604 1q25.2-q25.3 PTGS2 prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)
Mouse - 604 1 63.84 cM Ptgs2 prostaglandin-endoperoxide synthase 2
Rat - 604 13q21 Ptgs2 prostaglandin-endoperoxide synthase 2
Previous and Unofficial Names
Prostaglandin G2/H2 synthase-2
PTGS2
COX2
COX-2
PGH synthase 2
PGHS-2
PHS II
cyclooxygenase 2
cyclooxygenase-2
prostaglandin G/H synthase 2
prostaglandin H2 synthase 2
prostaglandin-endoperoxide synthase 2
Pghs2
prostaglandin G/H synthase
PHS-2
Tis10
Database Links
BRENDA
Ensembl Gene
Entrez Gene
ExplorEnz
GeneCards
GenitoUrinary Development Molecular Anatomy Project
Human Protein Reference Database
InterPro
KEGG BRITE Hierarchy
KEGG Gene
OMIM
PhosphoSitePlus
TreeFam
UniProtKB
Enzyme Reaction
EC Number: 1.14.99.1 Hydrogen donor + arachidonic acid + 2O2 = hydrogen acceptor + H2O + PGH2
Reaction 1:
arachidonic acid => PGG2 => PGH2
Reaction 2:
docosahexaenoic acid => PGH3
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
lumiracoxib Hs Inhibition 6.49 pKi 4
pKi 6.49 (Ki 3.2x10-7 M) [4]
celecoxib Hs Inhibition 8.7 pIC50 3
pIC50 8.7 (IC50 2x10-9 M) [3]
benzquinamide Hs Inhibition 8.32 pIC50 1
pIC50 8.32 (IC50 4.8x10-9 M) [1]
valdecoxib Hs Inhibition 8.3 pIC50 18-19
pIC50 8.3 [18]
pIC50 8.3 (IC50 5x10-9 M) [19]
flurbiprofen Hs Inhibition 8.0 pIC50 2
pIC50 8.0 (IC50 1x10-8 M) [2]
diclofenac Hs Inhibition 7.7 pIC50 5
pIC50 7.7 (IC50 2x10-8 M) [5]
meclofenamic acid Hs Inhibition 7.4 pIC50 10
pIC50 7.4 (IC50 4x10-8 M) [10]
carprofen Hs Inhibition 6.99 pIC50 9
pIC50 6.99 (IC50 1.02x10-7 M) [9]
Description: Inhibition of COX-2-induced conversion of arachadonic acid to 12-HHT.
meloxicam Hs Inhibition 6.31 pIC50 14
pIC50 6.31 (IC50 4.9x10-7 M) [14]
rofecoxib Hs Inhibition 6.1 – 6.5 pIC50 21
pIC50 6.1 – 6.5 [21]
nimesulide Hs Inhibition 6.22 pIC50 15
pIC50 6.22 (IC50 6x10-7 M) [15]
ketoprofen Hs Inhibition 6.16 pIC50 6
pIC50 6.16 (IC50 6.9x10-7 M) [6]
Description: Inhibition of COX2 in human whole blood.
etoricoxib Hs Inhibition 6.0 pIC50 16
pIC50 6.0 (IC50 1.1x10-6 M) [16]
ibuprofen Hs Inhibition 5.87 pIC50 20
pIC50 5.87 (IC50 1.35x10-6 M) [20]
aspirin Hs Inhibition 5.62 pIC50 17
pIC50 5.62 (IC50 2.4x10-6 M) [17]
naproxen Hs Inhibition 5.6 pIC50 13
pIC50 5.6 (IC50 2.5x10-6 M) [13]
ketorolac Hs Inhibition 4.22 – 6.92 pIC50 20
pIC50 6.92 (IC50 1.2x10-7 M) [20]
Description: Inhibition of human COX2 measured after pre-incubation of enzyme with compound.
pIC50 4.22 (IC50 6.05x10-5 M) [20]
Description: Instantaneous inhibition of human COX2 by compound (no pre-incubation).
suprofen Hs Inhibition 5.56 pIC50 6
pIC50 5.56 (IC50 2.75x10-6 M) [6]
mefenamic acid Hs Inhibition 5.54 pIC50 7
pIC50 5.54 (IC50 2.9x10-6 M) [7]
oxaprozin Hs Inhibition 4.44 pIC50 12
pIC50 4.44 (IC50 3.6x10-5 M) [12]
etodolac Hs Inhibition 4.28 pIC50 11
pIC50 4.28 (IC50 5.3x10-5 M) [11]
Description: Measured as LPS-induced PGE2 production in COX-1-inhibited human monocytes.
piroxicam Hs Inhibition 3.66 pIC50 22
pIC50 3.66 (IC50 2.18x10-4 M) [22]
phenylbutazone Hs Inhibition 3.55 pIC50 22
pIC50 3.55 (IC50 2.84x10-4 M) [22]
paracetamol Hs Inhibition - -
Inhibitor Comments
Carprofen is a COX-2 selective cyclooxygenase inhibitor, at least when comparing human COX-2 vs. ovine COX-1 in the same assay [8-9].
The data for etodolac in the table above is from Kato et al. (2001) [11]. In the same study etodolac's IC50 for COX-1 was reported to be >100 μM.
Piroxicam inhibits both cyclooxygenase isozymes [14], with maximum inhibition of PGE2 synthesis of approximately 60% for COX-2 and 35% for COX-1. Ketorolac is also a non-selective COX inhibitor.

References

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1. Auerbach SS, DrugMatrix® and ToxFX® Coordinator National Toxicology Program. National Toxicoligy Program: Dept of Health and Human Services. Accessed on 02/05/2014. Modified on 02/05/2014. DrugMatrix, https://ntp.niehs.nih.gov/drugmatrix/index.html

2. Bayly CI, Black WC, Léger S, Ouimet N, Ouellet M, Percival MD. (1999) Structure-based design of COX-2 selectivity into flurbiprofen. Bioorg. Med. Chem. Lett.9 (3): 307-12. [PMID:10091674]

3. Black WC, Brideau C, Chan CC, Charleson S, Cromlish W, Gordon R, Grimm EL, Hughes G, Leger S, Li CS et al.. (2003) 3,4-Diaryl-5-hydroxyfuranones: highly selective inhibitors of cyclooxygenase-2 with aqueous solubility. Bioorg. Med. Chem. Lett.13 (6): 1195-8. [PMID:12643942]

4. Blobaum AL, Marnett LJ. (2007) Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib. J. Biol. Chem.282 (22): 16379-90. [PMID:17434872]

5. Blobaum AL, Marnett LJ. (2007) Structural and functional basis of cyclooxygenase inhibition. J. Med. Chem.50 (7): 1425-41. [PMID:17341061]

6. Bézière N, Goossens L, Pommery J, Vezin H, Touati N, Hénichart JP, Pommery N. (2008) New NSAIDs-NO hybrid molecules with antiproliferative properties on human prostatic cancer cell lines. Bioorg. Med. Chem. Lett.18 (16): 4655-7. [PMID:18667313]

7. Heinrich DM, Flanagan JU, Jamieson SM, Silva S, Rigoreau LJ, Trivier E, Raynham T, Turnbull AP, Denny WA. (2013) Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3. Eur J Med Chem62: 738-44. [PMID:23454516]

8. Hieke M, Ness J, Steri R, Dittrich M, Greiner C, Werz O, Baumann K, Schubert-Zsilavecz M, Weggen S, Zettl H. (2010) Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity. J. Med. Chem.53 (12): 4691-700. [PMID:20503989]

9. Hieke M, Ness J, Steri R, Greiner C, Werz O, Schubert-Zsilavecz M, Weggen S, Zettl H. (2011) SAR studies of acidic dual γ-secretase/PPARγ modulators. Bioorg. Med. Chem.19 (18): 5372-82. [PMID:21873070]

10. Kalgutkar AS, Rowlinson SW, Crews BC, Marnett LJ. (2002) Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett.12 (4): 521-4. [PMID:11844663]

11. Kato M, Nishida S, Kitasato H, Sakata N, Kawai S. (2001) Cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: investigation using human peripheral monocytes. J. Pharm. Pharmacol.53 (12): 1679-85. [PMID:11804398]

12. Kawai S, Nishida S, Kato M, Furumaya Y, Okamoto R, Koshino T, Mizushima Y. (1998) Comparison of cyclooxygenase-1 and -2 inhibitory activities of various nonsteroidal anti-inflammatory drugs using human platelets and synovial cells. Eur. J. Pharmacol.347 (1): 87-94. [PMID:9650852]

13. Kolasa T, Brooks CD, Rodriques KE, Summers JB, Dellaria JF, Hulkower KI, Bouska J, Bell RL, Carter GW. (1997) Nonsteroidal anti-inflammatory drugs as scaffolds for the design of 5-lipoxygenase inhibitors. J. Med. Chem.40 (5): 819-24. [PMID:9057869]

14. Lazer ES, Miao CK, Cywin CL, Sorcek R, Wong HC, Meng Z, Potocki I, Hoermann M, Snow RJ, Tschantz MA et al.. (1997) Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity. J. Med. Chem.40 (6): 980-9. [PMID:9083488]

15. Ottanà R, Carotti S, Maccari R, Landini I, Chiricosta G, Caciagli B, Vigorita MG, Mini E. (2005) In vitro antiproliferative activity against human colon cancer cell lines of representative 4-thiazolidinones. Part I. Bioorg. Med. Chem. Lett.15 (17): 3930-3. [PMID:15993594]

16. Riendeau D, Percival MD, Brideau C, Charleson S, Dubé D, Ethier D, Falgueyret JP, Friesen RW, Gordon R, Greig G et al.. (2001) Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J. Pharmacol. Exp. Ther.296 (2): 558-66. [PMID:11160644]

17. Takahashi T, Miyazawa M. (2012) N-Caffeoyl serotonin as selective COX-2 inhibitor. Bioorg. Med. Chem. Lett.22 (7): 2494-6. [PMID:22386242]

18. Talley JJ, Bertenshaw SR, Brown DL, Carter JS, Graneto MJ, Kellogg MS, Koboldt CM, Yuan J, Zhang YY, Seibert K. (2000) N-[[(5-methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl]propanamide, sodium salt, parecoxib sodium: A potent and selective inhibitor of COX-2 for parenteral administration. J. Med. Chem.43 (9): 1661-3. [PMID:10794682]

19. Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY et al.. (2000) 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J. Med. Chem.43 (5): 775-7. [PMID:10715145]

20. Viegas A, Manso J, Corvo MC, Marques MM, Cabrita EJ. (2011) Binding of ibuprofen, ketorolac, and diclofenac to COX-1 and COX-2 studied by saturation transfer difference NMR. J. Med. Chem.54 (24): 8555-62. [PMID:22091869]

21. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. (1999) Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc. Natl. Acad. Sci. U.S.A.96 (13): 7563-8. [PMID:10377455]

22. Wilkerson WW, Copeland RA, Covington M, Trzaskos JM. (1995) Antiinflammatory 4,5-diarylpyrroles. 2. Activity as a function of cyclooxygenase-2 inhibition. J. Med. Chem.38 (20): 3895-901. [PMID:7562922]

How to cite this page

Eicosanoid turnover: COX-2 . Last modified on 08/05/2014. Accessed on 15/09/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1376.