COX-2 inhibitors are also prescribed for many forms of back pain. This article answers common questions about the side effects of COX-2 inhibitors and naproxen, another type of NSAID that has been called into question.
The article also examines recent research and explains the recommendations given by the U. See Potential Risks and Complications of Celecoxib.
The studies tested new uses of the drugs and have shown an increased risk for cardiovascular problems among certain groups of patients. For example, elderly patients and those who take the drugs for long periods of time tend to be more susceptible to known side effects such as gastrointestinal, kidney, and liver problems. The most important thing to remember is that each patient should meet with his or her physician to determine the best course of action based on individual risk factors, treatment needs, and previous experience with NSAIDs.
Several factors might have contributed to the failure of this trial. In particular, the selection of patients with advanced neuropathology and the short period of exposure to treatment may have played a role. However, it should be pointed out that no evidence is available to correlate these alternative mechanisms of NSAIDs with their clinical benefit reported inpopulation-based studies. COX-2 is constitutively expressed at high levels in brain and is specifically concentrated in pyramidal neurons which are vulnerable to AD pathology.
On the other hand, COX-1 is not constitutively expressed in brain at high levels but is upregulated in reactive microglia, the target for inflammatory suppression. It would be anticipated, therefore, that NSAIDs 1 rather than selective COX-2 inhibitors would be more likely to reduce the brain inflammation selectively 41 , 59 , However, it has been shown that COX-2 is up-regulated in brain dopaminergic neurons of both PD postmortem specimens and 1-methylphenyl-1,2,3,6-tertrahydropyridine MPTP mouse model of PD, and COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone involved in the pathogenesis of PD, suggesting that the inhibition of COX-2 may be a valuable target for the development of new therapies for PD aimed at slowing the progression of the neurodegenerative process Within the last two decades, the volume of literature on the structural types introduced as selective COX-2 inhibitors is enormous.
In this review, we have chosen to focus on the structure-activity relationship SAR and also various structural families of compounds, which have emerged within the last years. The chemical structures of COX-2 inhibitors are heterogenic so that a further classification of this group will be made in the following chapter.
Contrary to the classic NSAIDs Figure 8 , this new class of enzyme inhibitors is lacking a carboxylic group, thus effecting COX-2 affinity by a different orientation within the enzyme without formation of a salt bridge in the hydrophobic channel of the enzyme. In general classification, selective COX-2 inhibitors belong to two major structural classes: 1 Tricyclics also known as ortho-diarylheterocycles or carbocycles ; 2 Non-tricyclics.
All of the compounds in this class possess 1,2-diarylsubstitution on a central hetero or carbocyclic ring system with a characteristic methanesulfonyl, sulfonamido, azido, methanesulfonamide or pharmacophore-based tetrazole group on one of the aryl rings that plays a crucial role on COX-2 selectivity.
Coxibs such as Celecoxib, Rofecoxib, Valdecoxib and etc , belong to this common structural class 62 Figure 9. Compounds belonging to this class can be sub-classified based on the size and type of the central heterocyclic or carbocyclic ring system core.
Ring contraction to smaller carbocycles such as cyclobutenes also leads to potent COX-2 inhibitors as well as insertion of 5- and 6-membered carbocyclic or heterocyclic groups Figure A wide variety of 5-membered heterocycles can serve as a template for COX-2 inhibitors Figure 13 , i.
Knaus et al. Zarghi et al. Compounds [14] and [15] were potent COX-2 inhibitors which showed higher selectivity than celecoxib Besides, a group of 2-aryl, 3-benzyl- 1,3-oxazolidine or 1,3-thiazolidine ones possessing a SO2Me pharmacophore at the para-position of C-2 phenyl ring were reported by Zarghi et al.
New series of 2,4,5-triarylimidazoles possessing a SO 2 CH 3 pharmacophore at thepara position of C-4 phenyl ring has also been reported by Zarghi et al. Structure-activity relationship of this group showed that COX-2 inhibitory potency and selectivity is dependent on the nature of the substituent on the C-2 phenyl ring. Compound [18] possessing OH group at the para-position of the C-2 phenyl ring is the most potent and selective COX-2 inhibitor in this group 76 Figure One of the first structural types emerged in this category were pyridine series.
Li et al. Various n -substituted analogues were initially prepared to evaluate the effect of n -substitution in this category.
It was very clear that n -substitution was absolutely required for a good in-vitro COX-2 inhibitory potency since the unsubstituted analogues were not potent. An increase in the size of nitrogen substituent improved COX-2 inhibitory potency. Two potent and selective COX-2 inhibitors [20] and [21] have been identified from the pyridazinone template.
These two compounds also showed excellent efficacy in animal models of anti-inflammation, the rat paw edema and rat pyresis assays 78 Figure Pyrimidine-based COX-2 inhibitors were introduced by Orjales et al. Compound [22] was also the most selective pyrimidine derivative of the series with a calculated HWB selectivity index of 81, fold higher than rofecoxib 79 Figure Singh et al.
Compounds [23] and [24] were the most selective COX-2 inhibitors in this group The 2,3-diarylpyraneones [25] and 3,4-diarylpyraneones [26] containing a para-methylsulfonylpharmacophore have also shown to be the proper scaffolds for selective COX-2 inhibitors with potent oral anti-inflammatory activity 81 , 82 Figure Compound [27] was the most potent and selective COX-2 inhibitor among this group of compounds.
Apart from single 4-, 5- or 6-membered heterocyclic or carbocyclic rings, numerous examples of bicyclic or fused-ring systems as the central template have also appeared in the literature. Indoles [28] 84 , 2,3-diaryl-4H-chromenones [29] 85 , 2,3-diarylquinoxalines [30] 81 , benzo-1,3-dioxolanes [31] 86 , pyrazolo[1,5-b]pyridazines [32] 87 , pyrazolo[1,5-a]pyrimidines [33] 88 and pyrazolo[4,3-c]quinolinones [34] 89 are a few examples Figure A new group of 4,5,6,7-tetrahydro-1H-benzo[d]imidazoles possessing a SO 2 CH 3 pharmacophore at the para-position of C-2 phenyl ring has been reported by Zarghi et al.
Compound [36] possessing a fluoro atom at the para-position of N-1 phenyl ring is the most potent and selective COX-2 inhibitor in this group 91 Figure In a group of 4-carboxyl quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para-position of the C-2 phenyl ring in conjunction with various substituents at C-7 and C-8 quinoline ring, compound [37] was the most potent and selective COX-2 inhibitor, with potency and selectivity higher than the reference drug, celecoxib Furthermore, in a series of 2,3-diarylquinoline derivatives, compound [38] possessing a carboxyl group at C-4 position of the quinoline ring, showed the highest COX- 2 inhibitory potency and selectivity The rational for the design of these compounds was based on ketoprofen structure as a part of 2-aryl-quinolinecarboxylic acid scaffold.
Its regioisomer, compound [40] is also a very potent and selective COX-2 inhibitor in this series of compounds 94 Figure In addition to the classical tricyclic COX-2 inhibitors such as Coxib family, there are several non-classical structures which we here classify as non-tricyclics.
These series of compounds lack the cyclic central core. The central acyclic core may contain a two-membered or three-membered chain structure which is the basic point for sub-classification of these compounds. The 1,2-diarylethenes such as natural resveratrol analogues [41] 95 and also 2-alkyl-1,2-diarylolefines [42] 96 , 1,1,2-triarylethenes [43], [44], [45] 97 - 99 , acetylenes [46] , phenylazobenzenesulfonamides [47] and 4-phenyliminoethyl benzenesulfonamides [48] are included in this group Figure N-Butyl substituted compound [43] exhibited excellent potency and selectivity better than celecoxib.
In series of 1,1,2-triaryl E -ethenes having para-methylsulfonyl moiety on the C-1 phenyl ring, substitution at the C-2 phenyl ring with 4-fluoro substituent afforded [45] with better inhibitory potency and selectivity than celecoxib Figure The SAR data show that the isozyme selectivity in these compounds is dependent on the position of SO 2 Me group on C-1 phenyl ring, as well as the nature of the substituent on C-2 phenyl ring.
Compound [46] was the most potent and selective COX-2 inhibitor among these compounds. Chalcone derivatives are one of the most important groups of compounds in this category. Compound [49] was the most potent and selective COX-2 inhibitor in this group In the continuation of this research, Zarghi et al.
In these designed compounds, we utilized propenone scaffold instead of olefin moiety in 1,1,2-triaryl olefins. The Z isomers appeared to be more potent and selective inhibitors of the COX-2 isozyme. Z 4- methylsulfonyl phenyl -2,3-diphenylpropenone [52] showed the most potency and selectivity on COX-2 inhibition Figure A group of 1,3-diarylurea derivatives possessing a methylsulfonylpharmacophore at the para-position of the N-1 phenyl ring having a variety of substituents H, F, Cl, Me, OMe at the para-position of the N-3 phenyl ring were also reported by Zarghi et al.
The SAR results showed that the presence of a hydrogen acceptor group such as methoxy or fluorine substituent at the para-position of the N-3 phenyl ring may improve the selectivity and potency of COX-2 inhibition. Compound [53] was the most potent and selective COX-2 inhibitor in this group Figure Novartis group described conversion of diclofenac into lumiracoxib [55], which exhibits fold selectivity for COX-2 over COX-1 Figure Amongst the NSAIDs studied so far, the indomethacin template appears the most flexible in delivering COXspecific inhibitors following the functional group manipulations.
Various attempts have been made to shift the enzyme selectivity of indomethacin from COX-1 to COX-2 while keeping the potency on the same level and reducing the unwanted side-effects at the same time.
In principle, the strategy consisted of introducing larger substituents to fit into the active site volume of COX-2 Conversion of non-selective NSAIDs to esters and amides is a facile strategy for generating COX-2 inhibitors from known drugs but it has the limitation that indomethacin esters and possibly some amides may be hydrolyzed to indomethacin in-vivo.
Such compounds eliminate or minimize the generation of indomethacin in-vivo. Compounds [56] and [57] are the most potent and selective COX-2 inhibitors resulted from this strategy Figure Thus, it was though that more selective COX-2 inhibitors would have reduced the side effects.
In this review, the main emphasis was on the structure-activity relationship SAR and also various structural families of compounds, which have emerged within the last decade. In general classification, selective COX-2 inhibitors belong to two major structural classes: 1 Tricyclics, 2 Non-tricyclics. All of the tricyclic compounds possess 1,2-diarylsubstitution on a central hetero or carbocyclic ring system with a characteristic methanesulfonyl, sulfonamido, azido, methanesulfonamide or tetrazolepharmacophore group on one of the aryl rings that plays a key role on COX-2 selectivity.
Non-tricyclics lack the cyclic central core. The central acyclic core may contain a two-membered or three-membered chain structure. National Center for Biotechnology Information , U.
Iran J Pharm Res. Author information Article notes Copyright and License information Disclaimer. Received Sep; Accepted Oct. This article has been cited by other articles in PMC. Abstract Non-steroidal anti-inflammatory drugs NSAIDs are the competitive inhibitors of cyclooxygenase COX , the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins PGs. Biochemistry of prostanoids The biosynthesis of prostanoids, which include the prostaglandins PGs and thromboxanes, occurs in three steps: a the mobilization of a fatty acid substrate, typically arachidonic acid AA , from membrane phospholipids through the action of a phospholipase A2; b biotransformation of AA by cyclooxygenase in a bifunctional action which leads to the generation of unstable PGG2 by the cyclooxygenase reaction, and its immediate conversion into PGH2 by the same enzyme in a peroxidase reaction; c the conversion of PGH2 to specific prostanoids through the action of synthases and specific isomerases 3.
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Rofecoxib Vioxx voluntarily withdrawn from market. Burton B. Walker C. Int J Rheumatol. Published Dec 9. Arthritis Foundation. Solomon DH. Updated April 14, Updated February 26, Your Privacy Rights. To change or withdraw your consent choices for VerywellHealth. At any time, you can update your settings through the "EU Privacy" link at the bottom of any page. These choices will be signaled globally to our partners and will not affect browsing data.
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