1. University of Naples Federico II, Italy
2. Imperial College London, UK

Abstract

Prostaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase (COX, (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate,hydrogen-donor : oxygen oxidoreductase) activity, catalyses the formation of PGG₂ from arachidonic acid. Hydroperoxidase activity inherent in the enzyme catalyses the formation of PGH₂ from PGG₂. COX-1 and -2 can be nonselectively inhibited by ibuprofen, ketoprofen, naproxen, indomethacin and paracetamol (acetaminophen). PGH₂ may then be metabolised to prostaglandins and thromboxanes by various prostaglandin synthases in an apparently tissue-dependent manner.

Contents

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References

1. Adams JL, Smothers J, Srinivasan R and Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov 14: 603-22 [PMID:26228631]
2. Auerbach SS and DrugMatrix® and ToxFX® Coordinator National Toxicology Program.. National Toxicology Program: Dept of Health and Human Services. https://ntp.niehs.nih.gov/drugmatrix/index.html. Accessed on 02/05/2014.
3. Bayly CI, Black WC, Léger S, Ouimet N, Ouellet M and Percival MD. (1999) Structure-based design of COX-2 selectivity into flurbiprofen. Bioorg Med Chem Lett 9: 307-12 [PMID:10091674]
4. Beswick P, Bingham S, Bountra C, Brown T, Browning K, Campbell I, Chessell I, Clayton N, Collins S and Corfield J et al.. (2004) Identification of 2,3-diaryl-pyrazolo[1,5-b]pyridazines as potent and selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 14: 5445-8 [PMID:15454242]
5. Black WC, Brideau C, Chan CC, Charleson S, Cromlish W, Gordon R, Grimm EL, Hughes G, Leger S and Li CS et al.. (2003) 3,4-Diaryl-5-hydroxyfuranones: highly selective inhibitors of cyclooxygenase-2 with aqueous solubility. Bioorg Med Chem Lett 13: 1195-8 [PMID:12643942]
6. Blobaum AL and Marnett LJ. (2007) Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib. J Biol Chem 282: 16379-90 [PMID:17434872]
7. Blobaum AL and Marnett LJ. (2007) Structural and functional basis of cyclooxygenase inhibition. J Med Chem 50: 1425-41 [PMID:17341061]
8. Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
9. Bézière N, Goossens L, Pommery J, Vezin H, Touati N, Hénichart JP and Pommery N. (2008) New NSAIDs-NO hybrid molecules with antiproliferative properties on human prostatic cancer cell lines. Bioorg Med Chem Lett 18: 4655-7 [PMID:18667313]
10. Chowdhury MA, Abdellatif KR, Dong Y, Das D, Yu G, Velázquez CA, Suresh MR and Knaus EE. (2009) Synthesis and biological evaluation of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. Bioorg Med Chem Lett 19: 6855-61 [PMID:19884005]
11. Geisslinger G and Schaible HG. (1996) New insights into the site and mode of antinociceptive action of flurbiprofen enantiomers. J Clin Pharmacol 36: 513-20 [PMID:8809636]
12. Geusens P. (2009) Naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (CINOD). Expert Opin Biol Ther 9: 649-57 [PMID:19392579]
13. Gierse JK, McDonald JJ, Hauser SD, Rangwala SH, Koboldt CM and Seibert K. (1996) A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J Biol Chem 271: 15810-4 [PMID:8663121]
14. Heinrich DM, Flanagan JU, Jamieson SM, Silva S, Rigoreau LJ, Trivier E, Raynham T, Turnbull AP and 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 Chem 62: 738-44 [PMID:23454516]
15. Hieke M, Ness J, Steri R, Dittrich M, Greiner C, Werz O, Baumann K, Schubert-Zsilavecz M, Weggen S and Zettl H. (2010) Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity. J Med Chem 53: 4691-700 [PMID:20503989]
16. Hieke M, Ness J, Steri R, Greiner C, Werz O, Schubert-Zsilavecz M, Weggen S and Zettl H. (2011) SAR studies of acidic dual γ-secretase/PPARγ modulators. Bioorg Med Chem 19: 5372-82 [PMID:21873070]
17. Hinz B, Cheremina O and Brune K. (2008) Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J 22: 383-90 [PMID:17884974]
18. Hoshino J, Park EJ, Kondratyuk TP, Marler L, Pezzuto JM, van Breemen RB, Mo S, Li Y and Cushman M. (2010) Selective synthesis and biological evaluation of sulfate-conjugated resveratrol metabolites. J Med Chem 53: 5033-43 [PMID:20527891]
19. Imanishi J, Morita Y, Yoshimi E, Kuroda K, Masunaga T, Yamagami K, Kuno M, Hamachi E, Aoki S and Takahashi F et al.. (2011) Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor. Biochem Pharmacol 82: 746-54 [PMID:21745460]
20. Inagaki M, Tsuri T, Jyoyama H, Ono T, Yamada K, Kobayashi M, Hori Y, Arimura A, Yasui K and Ohno K et al.. (2000) Novel antiarthritic agents with 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) skeleton: cytokine suppressive dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase. J Med Chem 43: 2040-8 [PMID:10821716]
21. Janusz JM, Young PA, Scherz MW, Enzweiler K, Wu LI, Gan L, Pikul S, McDow-Dunham KL, Johnson CR and Senanayake CB et al.. (1998) New cyclooxygenase-2/5-lipoxygenase inhibitors. 2. 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: variations of the dihydrobenzofuran ring. J Med Chem 41: 1124-37 [PMID:9544212]
22. Kalgutkar AS, Rowlinson SW, Crews BC and Marnett LJ. (2002) Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 12: 521-4 [PMID:11844663]
23. Kassab SE, Khedr MA, Ali HI and Abdalla MM. (2017) Discovery of new indomethacin-based analogs with potentially selective cyclooxygenase-2 inhibition and observed diminishing to PGE2 activities. Eur J Med Chem 141: 306-321 [PMID:29031075]
24. Kato M, Nishida S, Kitasato H, Sakata N and Kawai S. (2001) Cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: investigation using human peripheral monocytes. J Pharm Pharmacol 53: 1679-85 [PMID:11804398]
25. Kawai S, Nishida S, Kato M, Furumaya Y, Okamoto R, Koshino T and 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: 87-94 [PMID:9650852]
26. Kiefer JR, Pawlitz JL, Moreland KT, Stegeman RA, Hood WF, Gierse JK, Stevens AM, Goodwin DC, Rowlinson SW and Marnett LJ et al.. (2000) Structural insights into the stereochemistry of the cyclooxygenase reaction. Nature 405: 97-101 [PMID:10811226]
27. Kolasa T, Brooks CD, Rodriques KE, Summers JB, Dellaria JF, Hulkower KI, Bouska J, Bell RL and Carter GW. (1997) Nonsteroidal anti-inflammatory drugs as scaffolds for the design of 5-lipoxygenase inhibitors. J Med Chem 40: 819-24 [PMID:9057869]
28. Kramer JS, Woltersdorf S, Duflot T, Hiesinger K, Lillich FF, Knöll F, Wittmann SK, Klingler FM, Brunst S and Chaikuad A et al.. (2019) Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain. J Med Chem 62: 8443-8460 [PMID:31436984]
29. Kumar R, Saha N, Purohit P, Garg SK, Seth K, Meena VS, Dubey S, Dave K, Goyal R and Sharma SS et al.. (2019) Cyclic enaminone as new chemotype for selective cyclooxygenase-2 inhibitory, anti-inflammatory, and analgesic activities. Eur J Med Chem 182: 111601 [PMID:31445233]
30. Lazer ES, Miao CK, Cywin CL, Sorcek R, Wong HC, Meng Z, Potocki I, Hoermann M, Snow RJ and 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: 980-9 [PMID:9083488]
31. Look GC, Schullek JR, Holmes CP, Chinn JP, Gordon EM and Gallop MA. (1996) The identification of cyclooxygenase-1 inhibitors from 4-thiazolidinone combinatorial libraries. Bioorg Med Chem Lett 6: 707-712
32. Migliore M, Habrant D, Sasso O, Albani C, Bertozzi SM, Armirotti A, Piomelli D and Scarpelli R. (2016) Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies. Eur J Med Chem 109: 216-37 [PMID:26774927]
33. Ochi T, Motoyama Y and Goto T. (2000) The analgesic effect profile of FR122047, a selective cyclooxygenase-1 inhibitor, in chemical nociceptive models. Eur J Pharmacol 391: 49-54 [PMID:10720634]
34. Ottanà R, Carotti S, Maccari R, Landini I, Chiricosta G, Caciagli B, Vigorita MG and Mini E. (2005) In vitro antiproliferative activity against human colon cancer cell lines of representative 4-thiazolidinones. Part I. Bioorg Med Chem Lett 15: 3930-3 [PMID:15993594]
35. Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW and Miyashiro JM et al.. (1997) Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). J Med Chem 40: 1347-65 [PMID:9135032]
36. Riendeau D, Percival MD, Brideau C, Charleson S, Dubé D, Ethier D, Falgueyret JP, Friesen RW, Gordon R and 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: 558-66 [PMID:11160644]
37. Riendeau D, Salem M, Styhler A, Ouellet M, Mancini JA and Li CS. (2004) Evaluation of loxoprofen and its alcohol metabolites for potency and selectivity of inhibition of cyclooxygenase-2. Bioorg Med Chem Lett 14: 1201-3 [PMID:14980665]
38. Singh P, Kaur S, Kaur J, Singh G and Bhatti R. (2016) Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent. J Med Chem 59: 3920-34 [PMID:27019010]
39. Smith CJ, Zhang Y, Koboldt CM, Muhammad J, Zweifel BS, Shaffer A, Talley JJ, Masferrer JL, Seibert K and Isakson PC. (1998) Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA 95: 13313-8 [PMID:9789085]
40. Takahashi T and Miyazawa M. (2012) N-Caffeoyl serotonin as selective COX-2 inhibitor. Bioorg Med Chem Lett 22: 2494-6 [PMID:22386242]
41. Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF and 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: 775-7 [PMID:10715145]
42. Uddin MJ, Xu S, Crews BC, Ghebreselasie K, Banerjee S and Marnett LJ. (2020) Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors ACS Med Chem Lett
43. Viegas A, Manso J, Corvo MC, Marques MM and 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: 8555-62 [PMID:22091869]
44. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA and 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 USA 96: 7563-8 [PMID:10377455]
45. Wilkerson WW, Copeland RA, Covington M and Trzaskos JM. (1995) Antiinflammatory 4,5-diarylpyrroles. 2. Activity as a function of cyclooxygenase-2 inhibition. J Med Chem 38: 3895-901 [PMID:7562922]
46. Zhang Z, Ghosh A, Connolly PJ, King P, Wilde T, Wang J, Dong Y, Li X, Liao D and Chen H et al.. (2021) Gut-Restricted Selective Cyclooxygenase-2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer. J Med Chem 64: 11570-11596 [PMID:34279934]
47. Zhou H, Liu W, Su Y, Wei Z, Liu J, Kolluri SK, Wu H, Cao Y, Chen J and Wu Y et al.. (2010) NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling. Cancer Cell 17: 560-73 [PMID:20541701]
48. Zou J, Jin D, Chen W, Wang J, Liu Q, Zhu X and Zhao W. (2005) Selective cyclooxygenase-2 inhibitors from Calophyllum membranaceum. J Nat Prod 68: 1514-8 [PMID:16252917]