THE DEVELOPMENT OF COX-1 AND COX-2 INHIBITORS: A REVIEWHTML Full Text
THE DEVELOPMENT OF COX-1 AND COX-2 INHIBITORS: A REVIEW
Rahul Kumar Vishwakarma and D. S. Negi *
Department of Chemistry, H. N. B. Garhwal University (A Central University), Srinagar Garhwal - 249161, Uttarakhand, India.
ABSTRACT: NSAIDs (Non-steroidal anti-inflammatory drugs) show its effect by preventing prostaglandin synthesis, which reasons ulcer complications and mucosal damage all over the gastrointestinal tract. The world’s most accepted drug was aspirin for treatment of pain and inflammation without knowing that it has the ability to inhibit prostaglandin production by inhibiting the cyclooxygenase enzyme for the treatment of pain and inflammation, until the late 1970s. The discovery of cyclo-oxygenase isoenzyme (COX-1 and COX-2), and their distinct function leads to the development of COX-1 and COX-2 selective inhibitors without any gastrointestinal toxicity. Initial intimations of the second form of cyclooxygenase (COX-2), which has different sensitivity for other drugs like aspirin, finally accompanied in a stimulating period of cyclooxygenase inhibitor discovery, concluding in the overview of an absolutely new generation of anti-inflammatory drugs. The aim of this paper is to review the development of COX-1 and COX-2 inhibitors. This paper also reviews that, what are the importance and history of natural products in the treatment of inflammation as COX-1 and COX-2 inhibitor.
COX-1,COX-2, NSAIDs, Aspirin, Cyclooxygenase-inhibitors
INTRODUCTION: Responsive phase of hyperemia and exudation of blood vessels consequences into inflammation, which leads swelling, consequent redness, heat, and pain in the tissue due to bacterial attack and many more causes like chemical hazards or physical injury 1. Inflammation is a tissue reaction by the body against damage, which comprises a multifaceted display of enzyme initiation, arbitrator issue, cell immigration, extravasations of fluid, repair, and breakdown of tissue 2.
There are three components of the inflammatory response, which have been identified 3, 4, and these may involve chemotactic factors 6, 7 vasoactive substances 5, degradative enzymes and superoxide 8 and the neuropeptide substance P 9. Non-steroidal anti-inflammatory drugs (NSAIDs) works by inhibiting prostaglandin synthesis, which causes ulcer complications and mucosal damage throughout the gastrointestinal tract 10.
Earlier it is known that COX enzymes are two types, one prevailing at locations of inflammation (COX-2) and one mostly occurs in the gastrointestinal tract (COX-1). This discovery shows the imperative role of healing advancement of COX-2 inhibitors 11. Later it is proved that COX happens in three isoforms. The first one is COX-1, which is responsible for immediate PG synthesis on basal, and upon stimulation, that also arises at high AA concentrations. COX-2 is tempted by growth and cytokines factors and mainly engaged in the regulation of inflammatory responses. COX-3, a splice variant of COX-1, mostly occurs in heart and brain 12-15. Inhibition of prostaglandin synthesis occurs by the central mechanism by which NSAIDs reduce inflammation and pain in arthritis and other inflammatory conditions. For many years, there is a discernment until the discovery of COX-1 and COX-2 that without gastrointestinal damage, NSAIDs could not show their therapeutic treatment 16-19. Thus, the discovery of cyclo-oxygenase isoenzyme (COX-1 and COX-2) and their function leads the development of COX-1 and COX-2 selective inhibitors without any gastrointestinal toxicity.
The world’s most accepted drug was aspirin for treatment of pain and inflammation without knowing that it has ability to inhibit prostaglandin production by inhibiting the cyclooxygenase enzyme for the treatment of pain and inflammation until the late 1970s. Initial intimations of a second form of cyclooxygenase (COX-2), which has different sensitivity for other drugs like aspirin, finally accompanied in a stimulating period of cyclooxygenase inhibitor discovery, concluding in the overview of an absolutely new generation of anti-inflammatory drugs 20. Numerous medicinal plant classes are commonly used in traditional medicine as inflammatory therapies. There are demonstrative anti-inflammatory herbs in nearly each family in the plant kingdom. Many of these plants have proven oral and documented evidence of their use in the medication of inflammatory ailments from old times 21.
COX-1 and COX-2 Concept: The morphological structure of COX-1 and COX-2 are shown in Fig. 1 with their catalytic active site.
FIG. 1: MORPHOLOGY OF COX-1 (LEFT) AND COX-2 (RIGHT) ENZYME 22
Tricyclic COX-2 selective inhibitor like Refocoxib, Celecoxib, and others act by blocking the COX-2 pocket. The selectivity is achieved due to the heavy size of the tricyclic C0X-2 inhibitor. Another important difference is the presence of leucine in COX-2 at the place of phenylalanine of COX-1, which shows greater flexibility in the upper side of the active site in COX-2. NSAIDs bind to COX-1 by reversible hydrogen-bonding and inhibition by simple steric hindrance, which leads to a great variation between COX-1 and COX-2, and in this way, selectivity can be achieved 23, 24. Studies of fluorescence quenching suggest that the outcome of COX-2 inhibitors is time-dependent which depends upon an active process with blocking of the lower enzyme site 25. Due to the presence of COX-2 mostly in the perinuclear envelope and COX-1 in the perinuclear membranes and endoplasmic reticulum (ER) the accessibility of the amino acid (AA) released by different PLA2 enzymes varies for each COX 26, 27. It was showed by Kulmacz and Wang in 1995 that COX-2 could show dominant catalysis at low hydroperoxide levels whereas COX-1 proceed at high hydroperoxide levels 28, 29. It is therefore believable that limited AAs accessibility in specific cellular conditions COX-2 activity is favored 30, 31. As another option, it has been projected that both COX-1 and COX-2 exhibit different attachment to the specific terminal prostanoid synthases. This thought was primarily recommended for link between COX isoenzymes and PGE synthases enzymes (PGES) and then between COX isoenzymes and other terminal prostanoid synthases 32. So far, three enzymes that catalyze the formation of PGE2 from PGH2 somewhat exactly have been recognized, namely membrane-bound PGES (mPGES) -1 33, 34, mPGES-2 35, and cytosolic PGES (cPGES) 32.
Prostaglandin Synthesis and Check Points for their Inhibition: Synthesis of prostaglandins shows a complex reaction mechanism which involves very specific conditions and occurs with suitable enzyme catalysis. The synthesis of prostaglandins and a possible checkpoint for NSAIDs to inhibit or regulate the synthesis is described in Fig. 2, as shown below.
Further, the produce PGE2 binds one or more its four specific receptor that is EP-1 to EP-4 to show its action 36.
FIG. 2: FATE OF SYNTHESIZED PGE2 AND CHECKPOINT FOR NSAIDS RE-PRODUCE 38
Next to all these, cytosolic enzymes, specifically 15-ketoprostaglandin Δᶦᶟ-reductase and 15-hydroxyprostaglandin dehydrogenase metabolized the excess of synthesized PGE2 because they could not be stored. In the case of cancer, 15-hydroxy-prostaglandin dehydrogenase is deregulated 37.
The Development of Field and Discovery of COX-2: The structural analysis of COX, that it has dual hydroperoxidase nature and cyclooxygenase activity 39, is suspecting and need further study for complete understanding. COX is dimeric membrane-bound protein, which has many encounters for purification and were not sequenced until 1988 40, 41. Additional issues obscuring the explanation of efficiency variances comprised the huge dissimilarities in assay environments which was used by various groups and variances in the kinetics of the COX inhibitors; these are still a problem today. Some of COX- inhibitors shows ‘competitive reversible’ inhibition, while others displayed uncommon inhibitory effects for instance the ‘competitive non-reversible’ inhibition that is detected specifically indomethacin group drugs 42. Among all the groups, only aspirin shows a mechanism in which it irreversibly acetylated a seine residue (Ser530) for the cyclooxygenase inhibition. This discovery strengthened the thought expressed by many groups that the non-steroidal anti-inflammatory drugs were a structurally diverse group of drugs with extensively dissimilar pattern of inhibition activity. So, it is clear that alterations in inhibitory power could be the outcome of reasons other than the isozymes existence 43, 44.
Deep analysis of inflammation in rabbit kidney induced by ligation of the urethra shows that 45 that the contaminated organ surprisingly developed a massive ability to generate prostaglandins because of de novo synthesis of the fresh enzyme, but there was no proposal shown that the new enzyme was a different form 46, 47. In the next few years, the occurrence of two discrete forms of COX in brain tissue was established, which shows different sensitivities to indomethacin 48. Different pharmacological analysis in gastrointestinal tissue also supports the fact that NSAIDs have variable selectivity for inhibition in dissimilar tissues 49.
COX gm RNA and de novo synthesis of an enzyme are induced during the medication of vascular smooth muscle cells with epidermal growth factor 50 or fibroblast and monocytes with early inflammatory inducements like as interleukin-1 51, 52 or lipopolysaccharide 53. Needleman’s and his coworker stated “Clearly, those putative enzyme pools may arise as different gene products, possibly through the expression of different COX genes” in his paper 54. It is also reportable that glucocorticoids inhibit the initiation of this new COX isoenzyme while the amount of enzyme remains unchanged in the cells 55. Although, it was also reported that one of the two isoforms of rat ovary was regulated by hormones, using immunological techniques 56.
After the development of field, the next work was the identification of different forms of COX enzyme. Simmons and his co-workers recognized that there is a specific mRNA transcript which was coded for protein synthesis while examining the appearance of early response genes in fibroblast transformed with Rous, which had a from top to bottom sequence similarity, but dissimilar to the seminal vesicle COX enzyme 57. In this way, a COX isozyme had been discovered. At the same time, Herschman and his colleagues revealed a specific cDNA which encoded a protein with a foretold structure similar to COX-1during the analysis of phorbol-ester-induced genes in Swiss 3T3 cells 58 and also explained that the product of this gene is a cyclooxygenase enzyme 59 which initiation was inhibited by dexamethasone 60. Correspondingly, revealing results are also showed in cultured rat mesangial cells 61, mouse fibroblasts 62, RAW 264.7 cells 63, the ovary 64, 65, rat alveolar macrophages 66, 67 and other cell types 68.
Finally, Needleman’s group concluded that the inflammation is an inducible form of COX, which had been cloned by both Simmons and Herschman 55. Therefore, on the basis of evidence, it is obvious that the stimulated form of the cyclooxygenase appeared basically in the brain named COX-2 69. COX-1/2mRNA differentially appears 70 in human tissues, and both the genes have a dissimilar chromosomal pattern in rodents 71 and humans72. And further promoter examination assured an ultimate variance between the two isoforms of COX, that is, COX-2 promoters become active on cellular stress and inactive by glucocorticoids 73; however, COX-1 mostly appeared in the gastrointestinal tract of rat, dog and monkey 74. So, on the basis of the above facts, COX-2 blocking should be the ideal therapeutic application of NSAIDs, whereas COX-1 blocking leads problems like gastric ulcer and decrease in platelet aggregation75-77. If these schemes are true, then a selective COX-2 inhibitor would be an ideal drug. But most of the NSAIDs in practice inhibited both the isoforms with a higher or lower extent, but drugs like as 6-MNA and BF389 also show some selectivity of action 78.
COX-2 as a Therapeutic Target for Inflammation, Cancer and Alzheimer's Disease: PGEs cause exudation of plasma, irritation, and pain in a synergistic manner with the involvement of enzyme and another cofactor during inflammation 79. Arthritis is a form of inflammation in animals that causes induction of COX-2 and believed to be accountable for the rise in PG production 80. COX-2 induction has been recognized in rheumatoid arthritis, and osteoarthritis affected cartilage in human 81. PGEs sensitize peripheral sensory nerve endings positioned at the site of inflammation 82, which causes pain during inflammation. It is also thought that COX products accountable for the transmission of pain responses through spinal cord 83, 84.
Though, it is not clear how COX isoforms involved in pain during inflammation 85. COX-2 inhibitors (e.g., DFU) with a high degree of selectivity inhibit hyperalgesia (pain) in rats 86. Actually, COX-2 induction in the spinal cord may induce the process of sensing pain, which has been demonstrated to inflammatory inducements in the paw in rats 87, 88. In humans, COX-2 selective inhibitors like as rofecoxib shows the analgesic effect when used during post-dental surgery 89.
Giovannucci and his colleagues find that a relatively low dose of NSAIDs (aspirin) for a long time decreases the risks of developing colon cancers in a patient; nevertheless, the mechanism is not well known 90, 92. This beneficial effect of NSAIDs (COX-2) had been shown by Smalley and his colleague in case of adenocarcinomas in human 91, by DuBois groups in isolated cells in culture 92 and by Williams in animal models 93. In all these cases, the COX-2 level increases. COX-2 has been recognized in other cancers such as oesophageal 94, gastric 95, and pancreatic cancer 96.
The other beneficial effect of NSAIDs related to COX suppression activity is to decreases the danger of evolving Alzheimer's disease 97 and reduce inflammation such as paracetamol without any side effect 98. It had been shown by the Pasinetti & Aisen group that COX-2 appearance and extent is increased in the frontal cortex of brains in the case of Alzheimer's disease 99. Additionally, PPAR-γ receptor and both isoform of COX induction is also raised in the temporal cortex of brains in theses case 100. Therefore, NSAIDs may show effective treatment for Alzheimer's disease due to its ant-platelet properties 101. Though studies on animals had shown that COX-2 is stimulated in neurons after kainic acid-induced seizures that are susceptible to apoptosis 102.
NSAIDs and COX-1/2 Active Compounds: The drugs celecoxib and rofecoxib were revealed on a rational basis for COX-2 selectivity 103-105. Three-dimensional structure forecast for Cyclooxygenase-1 and Cyclooxygenase-2 demonstrate the similarity between these isoforms that how problematic to attain novel selectivity and, therefore, how predicational the rational discovery of these drugs 106-108. Many compounds that are synthesized and screened in-vitro for COX inhibition 109 are described in the following Table 1.
TABLE 1: SELECTIVITY OF NSAIDS AS COX INHIBITOR 109
|Compounds||COX-1 (IC₅₀ in uM)||WBA-COX-2 (IC₅₀ in uM)||WHMA-COX-2 (IC₅₀ in uM)|
Note -: Group (A) compounds show high blocking activity for COX-1as well as for COX-2 but a low degree COX-2 selectivity. Group (B) compounds show high blocking activity for COX-1 and COX-2 with greater than 5 fold selectivity for COX-2 (WHMA/COX-1<0.2). Group (C) compounds show a low degree of blocking activity for COX-1as as well as for COX-2. Group (D) shows a low degree of blocking activity for COX-1as well as COX-2 which further study is required for confirmation 109
GROUP A COMPOUND
GROUP B COMPOUND
GROUP C COMPOUND
GROUP D COMPOUND
FIG. 3: STRUCTURE OF NSAIDS AND SOME COX-2 SELECTIVE COMPOUNDS
Note: Group (A) compounds, Group (B) compounds, Group (C) compounds and Group (D) compounds are described in Table 1
There are many phytochemicals that had been isolated structurally and pharmacologically characterized as an anti-inflammatory remedy in Table 2. Some of them show remarkable activity while others show mild, with a gastrointestinal ulcer side effect.
FIG. 4: STRUCTURE OF NSAIDS AND SOME COX-2 SELECTIVE COMPOUNDS ISOLATED FROM PLANT
TABLE 2: ISOLATED ANTI-INFLAMMATORY PLANT CONSTITUENTS
|Compound||Plant (part)||Anti-inflammatory activity||COX Inhibition (IC50 in uM)|
|Fagaramide (piperonyl-4-acrylicisobutylamide) 110||Zanthoxylum zanthoxyloides (Root)||(+)||2.06|
|Lupeol lupeol lineolate 111, 112||Crataeva religiosa (Stem bark)||(+)||n.d.|
Methoxyflavones (jaceosidin, eupatorin, chrysoeriol, and diosmetin) 113
|(+) – Pinitol 114||Abies pindrow Spach (Leaves)||(+)||n.d.|
|Premnazole 115||Gmelina arborea (Leaves), Premna integrifolia (Leaves)||(+)||n.d.|
|3, 4-seco-D:Bfriedobacchara-4, 21-dien-3ol 116||Camellia sasanqua
|Tirucall–5, 7, 24–trine-3-beta–ol,
Isoeuphol, Isotirucallol, (24R)–24, 25–epoxybutyrospermol, (24S)– 24, 25–epoxybutyrospermol, Isoaglaiol 117
|(+)-Usnic acid 118||Roccella montagnei (Whole plant)||(+)||n.d.|
|Zanhasaponins A, B and C
Cyclitol (pinitol) 119
|Zanha Africana (Root bark)||(+)||n.d.|
|Cycleanine 120||Stephania glabra (Tuber)||(+)||n.d.|
CONCLUSION: COX-1 and COX-2 involve in chronic pain associated with rheumatoid or osteo-arthritis, in protection in some form of cancer and Alzheimer’s diseases. Though, link between anti-inflammatory properties of COX isoforms and these diseases is not totally understood which may be good research field for interested researcher.
NSAIDs such as Celocoxib (Pyrazolones derivative) and Rofecoxib shows a great selectivity for COX-2 isoform, therefore synthesis of analogues of these category drugs may have a good selectivity for COX-2 isoform, that could be hit and try in future.
There are many plants for which intrinsic anti-inflammatory activity is anecdote from other known pharmacological activities related to variation of the complex inflammatory response. At present, there is escalating scientific evidence for the anti-inflammatory activity of many plants. There are many plants for which the anti-inflammatory activity has been widely studied while primary sign has been recognized for others. There are many phytochemicals which had been isolated structurally and pharmacologically characterized as an anti-inflammatory remedy. But there are many plants which shows anti-inflammatory activity while their COX inhibition property is not well recognized. So, further analysis for COX inhibition for these plants may be the interesting zone for natural product researchers.
ACKNOWLEDGEMENT: The authors express their sincere thanks to Professor D. S. Negi for his keen interest in the work and to the CSIR-HRD, New Delhi for providing the financial assistance in form of a Junior Research Fellowship (CSIR-NET JRF).
CONFLICTS OF INTEREST: There is no conflict of interest from any author.
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How to cite this article:
Vishwakarma RK and Negi DS: The development of COX-1 and COX-2 inhibitors: a review. Int J Pharm Sci & Res 2020; 11(8): 3544-55. doi: 10.13040/IJPSR.0975-8232.11(8).3544-55.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
R. K. Vishwakarma and D. S. Negi *
Department of Chemistry, H. N. B. Garhwal University (A Central University), Srinagar Garhwal, Uttarakhand, India.
26 October 2019
04 March 2020
19 April 2020
01 August 2020