Iranian Journal of Pharmaceutical Research (2011), 10 (4): 655-683 Copyright © 2011 by School of Pharmacy

Received: September 2011 Shaheed Beheshti University of Medical Sciences and Health Services
Accepted: October 2011

Review Article

Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships

Afshin Zarghi* and Sara Arfaei

Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University

of Medical Sciences, Tehran, Iran.

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). Their use is associated with the side effects
such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action
of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects
arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2
inhibitors would have reduced side effects. Based upon a number of selective COX-2
inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with
improved gastric safety profile. However, the recent market removal of some COXIBs
such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the
researchers to explore and evaluate alternative templates with COX-2 inhibitory activity.
Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy
and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to
attract investigations on the development of COX-2 inhibitors. This review highlights the
various structural classes of selective COX-2 inhibitors with special emphasis on their
structure-activity relationships.

Keywords: NSAIDs; Cyclooxygenase; Selective COX-2 Inhibitors; Coxibs; SAR.

Introduction enzyme was first identified as the therapeutic

target of NSAIDs by Vane in 1971, showing
Non-steroidal anti-inflammatory drugs that these anti-inflammatory substances block
(NSAIDs) are among the most widely used the biosynthesis of prostaglandins (PGs) that
therapeutics. Through their anti-inflammatory, contribute to a variety of physiological and
anti-pyretic and analgesic activities, they pathophysiological functions (2).
represent a choice treatment in various
inflammatory diseases such as arthritis, Biochemistry of prostanoids
rheumatisms as well as relieving the pains of The biosynthesis of prostanoids, which include
everyday life. From a historical viewpoint, the prostaglandins (PGs) and thromboxanes,
the first NSAID with therapeutic benefits was occurs in three steps: (a) the mobilization of
aspirin, which has now been used for more than a fatty acid substrate, typically arachidonic
100 years as a NSAID (1). The cyclooxygenase acid (AA), from membrane phospholipids
through the action of a phospholipase A2; (b)
* Corresponding author: biotransformation of AA by cyclooxygenase in a
E-mail: zarghi@sbmu.ac.ir bifunctional action which leads to the generation
Zarghi A and Arfaei S / IJPR (2011), 10 (4): 655-683

of unstable PGG2 by the cyclooxygenase most important PG which mediates the typical
reaction, and its immediate conversion into symptoms of inflammation: rubor, calor,
PGH2 by the same enzyme in a peroxidase tumor, dolor and functio laesa. Dilatation of
reaction; (c) the conversion of PGH2 to specific small blood vessels initiates the development
prostanoids through the action of synthases and of redness and heat; the increase in vascular
specific isomerases (3). (Figure 1). permeability causes the characteristic swelling
of tissues. It also produces hyperalgesia by a
Biological roles of prostaglandins sensitizing action on the peripheral terminals of
Prostaglandins (PGs) are hormone-like sensory fibers. Moreover, PGE2 acts on neurons
bioactive substances mediating autocrine and and contributes to the systemic responses to
paracrine signaling over the short distances inflammation such as fever, fatigue and pain
and are involved in many physiological and hypersensitivity (10, 11).
pathological processes. They act via high-
affinity G protein-coupled receptors: four EP The COX isozymes
receptors for PGE2 termed EP1-EP4, IP receptor Despite the wide use of NSAIDs over the
for prostacyclin, DP receptor for PGD2, FP last century, their mechanism of action was
receptor for PGF2α. These receptors are linked not fully understood until 1971 when Vane
to the different signal transduction pathways (4). identified their molecular target, the COX
In addition, peroxisome proliferator-activated enzyme. In the early 1990s, a second isoform
receptors (PPAR) have been identified as novel (COX-2) was discovered, distinct from the first
intracellular PG receptors (5). Once a prostanoid one, then renamed COX-1. COX-1 and COX-
is formed, it exits the cell and then interacts 2 are isoenzymes (12). Since isoenzymes are
with G protein-coupled receptors, either on genetically independent proteins, the genes
the parent cell or on closely neighboring cells in humans for the two enzymes are located
to modulate the second messenger levels (6). on different chromosomes and show different
Although their tissue distribution depends on properties (13). COX-1 is expressed constitutively
the cellular enzymatic material, prostanoids are in many tissues and PGs produced by COX-1
involved in a very broad range of physiological mediate the “housekeeping” functions such as
and pathophysiological responses (7). cytoprotection of gastric mucosa, regulation of
In the cardiovascular system, PGD2 and renal blood flow and platelet aggregation. In
PGE2 as well as PGI2 are potent vasodilators contrast, COX-2 is not detected in most normal
whereas TXA2 displays vasoconstrictor tissues, but its expression is rapidly induced by
properties. TXA2 also plays a major role in the stimuli such as proinflammatory cytokines (IL-
induction of platelet aggregation while PGI2 1b, TNFα), lipopolysaccharides, mitogens and
presents anticoagulant properties. In the airways, oncogenes (phorbol esters), growth factors
PGF2α and TXA2 are bronchoconstrictors (fibroblast growth factor, FGF; platelet-derived
whereas PGI2 and PGE2 act as bronchodilators. growth factor, PDGF; epidermal growth factor,
In the GI tract, PGE2 and PGF2α as well as EGF), hormones (luteinizing hormone, LH)
PGI2 ensure the protection of the gastric mucosa and disorders of water-electrolyte hemostasis,
by lowering the acid secretions, enhancing the resulting in increased synthesis of PGs in
mucosal blood flow and stimulating the mucus inflamed and neoplastic tissues. Thus, the
formation and bicarbonate secretion. TXA2 inducible isozyme has been implicated in
induces the increased vascular permeability, pathological processes such as inflammation and
leading to edema. In the compromised kidney, various cancer types (14, 15).
PGE2 and PGI2, unlike TXA2, stimulate renal However, recent studies have shown that
blood flow and diuresis. PGE2 and PGF2α, in the relation between the two isoforms is not so
contrast to PGI2, strongly contract the uterine straightforward. Indeed, COX-1 may contribute
smooth muscle (8, 9). to the inflammation processes whereas COX-
Prostanoids also mediate body’s responses 2 is constitutively expressed in several tissues
to tissue injury or inflammation. PGE2 is the and organs such as brain (16), kidneys (17) and

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Phospholipase A2

Arachidonic acid
Cyclooxygenase
Reaction

COX Prostaglandin G2
Peroxidase
Reaction

Prostaglandin H2

Specific Isomerases
TXA2
PGF2α
PGE2 PGI2
PGD2

Figure 1. Biosynthesis of prostanoids.

reproductive tract (18) (Figure 2). or the inhibitors and the peroxidase one which
contains the heme cofactor. These sites are
Enzymatic structure distinct but functionally and structurally
The COX isoenzymes are membrane- interconnected (19) (Figure 3).
bound enzymes in the endoplasmic reticulum The cyclooxygenase active site is created by
(ER). The three dimensional structure of the a long hydrophobic channel that is the site of
ovine COX-1 was first reported in 1994 and non-steroidal anti-inflammatory drug binding.
the crystal structures of human and murine This active site extends from the membrane-
COX-2 quickly followed. COX functions as a binding domain (the lobby) to the core of the
homodimer and attempts to create monomeric catalytic domain (20, 21). The arachidonate-
species which have yielded only inactive binding site is located in the upper half of the
enzyme. The crystal structures of the COX channel, from Arg-120 to near Tyr-385. Ser- 530,
isoforms are quite structurally homologous positioned in the middle of the channel, is the
and consistent with a high sequence identity site of acetylation by aspirin (22). Three amino
(ca. 60%); the overall structures of COX-1 acid differences result in a larger (about 20%)
and COX-2 are highly conserved. The COX and more accessible channel, in COX-2. The
monomer consists of three structural domains: exchange of a valine at position of 523 in COX-
an N-terminal epidermal growth factor (EGF)- 2 for a relatively bulky isoleucine (Ile) residue
like domain, a membrane binding domain in COX-1 at the same position of the active site
(MBD) of about 48 amino acids in length of the enzyme, causes a structural modification.
which anchors the protein to one leaflet of This modification in the COX-2 enzyme allows
the lipid bilayer, and a large C-terminal the access to an additional side pocket, which
globular catalytic domain with the COX is a pre-requisite for COX-2 drug selectivity.
active site which accommodates the substrate Access to this side pocket is restricted in the

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Figure 2. Schematic presentation of the actions of cyclooxygenases (COX-1 and COX-2).

case of COX-1. In addition, the exchange of Ile- gene. The only difference is the retention of intron
434 for a valine in COX-2 allows a neighboring 1 of the COX-1 gene in COX-3 (Figure 5).
residue phenylalanine-518 (Phe-518) to swing COX-3, which contributes about 5% of total
out of the way, increasing further access to the COX-1, is a 65-kDa membrane protein whose
side cavity. There is another essential amino cyclooxygenase activity is about 80% lower
acid difference between the two isoforms, which than that of COX-1. This suggests that intron 1
does not alter the shape of the drug-binding site retention may modify the conformation of the
but rather changes its chemical environment. active site. Preferential expression of COX-3 in
Within the side pocket of COX-2 is an arginine the brain and heart has been reported (24, 25). In
in place of histidine-513 (His-513) in COX-1, addition to COX-3, two shorter variants without
which can interact with polar moieties. These cyclooxygenase activity have been identified,
differences between the COX active sites have PCOX-1a and PCOX-1b (Figure 5). The function
major implications for the selectivity profile of of these two inactive, truncated COX-1 variants
inhibitors (9, 10, 23) (Figure 4). is unknown (26).
The distinctive characteristic of COX-3 as
The third isoform compared to COX-1 and COX-2 is its greater
In 2002, the group of Daniel Simmons sensitivity to acetaminophen. Different studies
characterized and cloned a COX enzyme in have shown that acetaminophen has only weak
dog brain which, unlike COX-1 and COX-2, inhibitory actions on both COX-1 and COX-
was sensitive to inhibition with paracetamol 2 when tested on in-vitro experimental systems.
(acetaminophen). This COX enzyme was a variant However, it is a potent, selective inhibitor of
of COX-1 and derived from the same gene; it COX-3 and most likely produces analgesia by
was designated as COX-3 (24). This variant is inhibiting this enzyme (28). Non-steroidal anti-
produced by alternative splicing of the COX-1 inflammatory drugs (NSAIDs), such as diclofenac

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Figure 3. A: Space-filling model of COX-2 along with a Schematic presentation of different parts of cyclooxygenase enzyme. B: A
space-filling model of the COX-1 dimer viewed from the membrane plane. The EGF-like and MBD domains are colored green and gold,
respectively. The catalytic domains are colored two different shades of blue to highlight the dimer interface. Arg120 (purple), which is
part of the channel aperture, defines the beginning of the COX active site. Within one COX channel, a buried AA (yellow and red) is
shown (derived from (19).)

or ibuprofen, are also potent inhibitors of COX- at the nucleotide sequence level in humans has
3 expressed in cultured cells, but being highly been called to question. A recent sequencing
polar, they are unlikely to reach brain COX-3 study of the human COX-1 gene found that the
in effective concentrations. Moreover, selective first intron contained an additional nucleotide, as
COX-3 inhibitors, aminopyrine and antipyrine compared to canine COX-3. This difference may
have been shown to act centrally to cause their lead to a frameshift precluding translation into a
antipyretic and analgesic effects in mice. functional protein (29).
COX-3 is considered to play a key role in The identification of COX variants opens a
the biosynthesis of prostanoids known to be new chapter in NSAID pharmacology, which
important mediators in pain and fever. Drugs that may answer, among other things, how analgesic/
preferentially block COX-1 also appear to act on antipyretic drugs work. This may lead eventually
COX-3 (24). However, the existence of COX-3 to the development of new drugs that target the

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Figure 4. The COX-2 active site and its schematic representation (Figure composed using Accelrys ViewerLite 5.0).

desired pathway, thereby providing more precise healing process. So, selective COX-2 inhibitors
and more effective treatment. should be avoided in patients with gastric
susceptibility (34).
Side-effects of selective COX-2 inhibitors In addition, selective inhibitors of COX-2
The simplified paradigm of constitutive COX- depress prostacyclin (PGI2), an atheroprotective
1 and inducible COX-2 has many exceptions: agent, but not COX-1 derived thromboxane A2
COX-1 can be regulated during development, (TXA2), a proaggregatory and vasoconstrictor
whereas COX-2 is constitutively expressed mediator, which might predispose patients to
in the brain, reproductive tissues and kidney heart attack and stroke. Thus, the use of these
(30). In addition to its implication in the kidney compounds in cardiovascular diseases still
development, COX-2 plays an important role in requires vigilance (35). Rofecoxib (Vioxx) was
the regulation of renal function (perfusion, water withdrawn voluntarily by Merck from the market
handling, and renin release) in both normal and in September 2004 following the increased
paraphysiological conditions (i.e., in patients with cardiovascular risks observed in Adenomatous
liver cirrhosis, renal insufficiency or congestive Polyp Prevention on Vioxx (APPROVe) study.
heart failure). These patients are, therefore, at Subsequently, the sale of Bextra (valdecoxib)
risk of renal ischemia when NSAIDs and/or was also suspended by Pfizer in 2005. This
selective COX-2 inhibitors reduce vasodilatory raised a question on the safety of selective
PG synthesis (31). Moreover, cyclic hormonal COX-2 inhibitors. However, no increased risk
induction of COX-2 is important for ovulation of cardiovascular thrombotic events was evident
and, at the end of pregnancy, high uterine levels in Celecoxib Long Term Arthritis Safety Study
of COX-2 are necessary for the onset of labor. (CLASS) trial conducted on celecoxib (36),
As a result, like for classical NSAIDs, the use which is the only selective COX-2 inhibitor
of selective COX-2 inhibitors should be avoided available in U.S. market. A meta-analysis of
in the early stages of pregnancy whereas they published and unpublished tabular data from
should be useful in delaying premature delivery randomized trials revealed that selective COX-
(32, 33). 2 inhibitors and traditional NSAIDs (high dose
COX-2 may be involved in the ‘‘adaptative regimens of ibuprofen and diclofenac) have
cytoprotection’’ response in GI mucosa. When similar incidence of adverse cardiovascular
the latter is inflamed or ulcerated, COX-2 events (37). Various studies suggest that the
is rapidly induced at sites of injury where it cardiovascular toxicity associated with the
produces large amounts of PGs involved in the use of selective COX-2 inhibitors might be

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steroidal anti-inflammatory drugs (NSAIDs)

could be of benefit against the development
and growth of malignancies. Moreover, clinical
trials in patients with familial adenomatous
polyposis syndrome have shown the efficacy of
non-selective and selective COX-2 inhibitors
in the reduction of the number and the size of
colorectal polyps. Celecoxib has been approved
by FDA (Food and Drug Administration) as an
adjunct for the treatment of familial adenomatous
polyposis (FAP) (42).
However, a primary chemopreventive effect
Figure 5. Structure of COX-1 variants produced by alternate
has not been demonstrated yet. NSAIDs are
splicing (27). also supposed to have a preventive and growth
inhibitory effect in extra-colonic epithelial
malignancies. Several preclinical studies show
dependent on the dose as well as on the duration promising results with combination treatments
of treatment (38). The mechanism underlying of either chemotherapy or radiotherapy with
the adverse cardiovascular effects associated COX inhibitors. Preclinical studies with
with the use of COX inhibitors is due to an the simultaneous use of inhibitors of the
imbalance between COX-1 derived thrombotic epidermal growth factor receptor and COX-
thromboxane A2 (TXA2) in platelets and COX- 2 inhibitors have shown also promising
2 derived vasoprotective prostacyclin (PGI2) results. Encouraging results with the first
in endothelium (36). There should be > 95% clinical trials combining chemotherapy with
suppression of the platelet COX-1 before it can COX-2 inhibitors in patients with cancer in
be translated into clinically relevant platelet the advanced and neoadjuvant setting have
inhibition (39). All NSAIDs significantly recently been reported. However, NSAIDs
inhibit COX-2 at therapeutic dose but only few effects in cancer cells are mediated not only
traditional NSAIDs (aspirin and naproxen) are by COX enzymes but also by interactions with
able to show > 95% suppression of the platelet downstream effectors of COX-2 (42).
COX-1 at such dose. This explains why selective Hence, we can state that targeting the COX-2
COX-2 inhibitors as well as traditional NSAIDs pathway is a promising strategy in the prevention
show adverse cardiovascular effects (40). and treatment of solid tumors. Ongoing trials
It has also been shown that COX inhibition are expected to answer – at least partly – the
by NSAIDs, besides causing a reduction in the remaining questions concerning COX-2 and
synthesis of vasodilatory and gastroprotective cancer. Here, we focus on the rationale for
PGs leads to an up-regulation of AA metabolism using selective COX-2 inhibitors as anti-cancer
by the 5-LOX pathway, increasing the formation agents.
of LTs and contributing to inflammation and
NSAIDs-induced adverse effects such as Regulating COX-2 expression
asthma. Dual inhibition of COX-2 and 5-LOX Increased amounts of COX-2 are found
is, therefore, an interesting alternative to provide commonly in both premalignant and malignant
safer NSAIDs (9, 41). tissues (43). Overexpression of COX-2
appears to be a consequence of both increased
COX-2 and new therapeutic targets transcription and enhanced mRNA stability
COX-2 as a target for anticancer drug (44, 45). Oncogenes, growth factors, cytokines,
development chemotherapy and tumor promoters stimulate
Large epidemiological trials studying users COX-2 transcription via protein kinase C (PKC)
and non-users of aspirin have shown that and RAt Sarcoma-mediated (RAS-mediated)
cyclooxygenase (COX) inhibitors and non- signaling (Figure 6). Agents that interfere with

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Figure 6. Regulation of cyclooxygenase 2 (COX-2) in cancer.COX-2 is induced by a variety of stimuli including oncogenes (HER-2/
neu), growth factors (epidermal growth factor (EGF)), tumor promoters (phorbol esters and bile acids) and chemotherapy (taxanes).
Stimulation of either protein kinase C (PKC) or RAS signaling enhances mitogen-activated protein kinase (MAPK) activity, which in
turn, activates the transcription of COX-2. Several transcription factors, including activator protein 1 (AP-1) and nuclear factor kB (NF-
kB), mediate the induction of COX-2. By contrast, wild-type p53 suppresses transcription of COX-2. COX-2 is also regulated by post-
transcriptional mechanisms. The 30-untranslated region (30UTR) of COX-2 mRNA contains a series of sequences (AUUUA) known
as AU-enriched elements (AREs) that confer the message instability. Augmented binding of HuR, an RNA-binding protein, to these
elements is responsible, at least in part, for increased stability of COX-2 mRNA in tumors. In addition, prostaglandin E2 (PGE2) induces
COX-2 by activating the tyrosine kinase activity of the EGF receptor, but it is not known whether this positive feedback mechanism
is relevant in human tumors. Abbreviations: CBP, CREB binding protein; CRE, cAMP response element; ERK, extracellular signal
regulated kinase; JNK, Jun N-terminal kinase; MEK, MAPK kinase; NF-IL6, nuclear factor interleukin 6; PEA3, polyomavirus enhancer
activator 3; PI3K, phosphatidylinositol 3-kinase; PLA2, phopholipase A2; RNA Pol II, RNA polymerase II; TBP, TATA-binding protein
(derived from (46)).

microtubules, including taxanes, induce COX- suggest that the balance between activation of
2 by activating PKC and mitogen-activated oncogenes and inactivation of tumor suppressor
protein kinases (MAPKs) (Figure 6). Depending genes affects expression of COX-2 (46).
on the stimulus and cell type, a variety of There is growing evidence that post-
transcription factors including activator protein transcriptional mechanisms also determine
1 (AP-1), nuclear factor interleukin-6 (NF-IL6), COX-2 levels in neoplastic tissues. Oncogenes,
nuclear factor-kappaB (NF-kB), nuclear factor cytokines, growth factors and tumor promoters
of activated T-cells (NFAT) and polyomavirus induce COX-2 by enhancing mRNA stability
enhancer activator 3 (PEA3) can modulate in addition to the stimulating transcription.
the transcription of COX-2. Although many In human colon cancers, overexpression of
factors enhance COX-2 transcription, much COX-2 is a consequence of both increased
less is known about negative modulators. Wild- transcription and decreased mRNA turnover.
type, but not mutant, p53 markedly suppresses Interestingly, the activation of extracellular
the transcription of COX-2. These findings signal regulated kinase 1/2 (ERK1/2) and p38

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stabilize COX-2 mRNA in addition to the Their association with COX-2 inhibitors could
stimulating transcription (46). therefore be interesting in treating cancer (49).
EGFR and COX-2 pathways develop a real
The mechanisms by which COX-2 contributes cross talk: PG E2 stimulates EGFR signaling
to cancer via the shedding of active EGFR ligands from
COX-2 affects many processes that have been the plasma membrane but can also induce
implicated in different stages of carcinogenesis. EGFR transactivation directly via Src pathway
These include xenobiotic metabolism, cell stimulation. Conversely, EGFR transactivation
proliferation, angiogenesis, apoptosis, immune stimulates AP-1-mediated induction of COX-2
function and tumor invasiveness (15, 42) (Figure 7). expression and thus PG E2 expression resulting
in a loop of cross-stimulation (42, 50, 51).
Activation of carcinogens
The peroxidase part of COX can convert Prostaglandins and apoptosis
the procarcinogens to carcinogens and thus Apoptosis, the morphologically defined
initiate tumor formation. Substantial amounts form of programmed cell death, plays a crucial
of xenobiotics (natural non-human organic role in the carcinogenesis. The disegulation of
compounds) can be co-oxidized into mutagens this process can lead to abnormal survival of
by the peroxidase activity of COX (47). This cells and the increased risk of mutagenesis and
reaction could be relevant at organ sites that are oncogenesis (15).
exposed to tobacco carcinogens such as lung, COX-2-derived PGs regulate programmed
oral cavity and bladder. Similarly, estrogens, cell-death and reduce the apoptotic rate via
oxidized to diethylstilbestrol demonstrate inhibition of the mitochondrial apoptotic pathway
transforming and genotoxic activity. Moreover, characterized through reduced cytochrome c
the metabolism of the arachidonic acid release, attenuated caspase-9 and -3 activation
itself produces mutagens. Some by-products and upregulation of bcl-2 (15, 52). Additionally,
of the oxidation of arachidonic acid, like increased prostanoid generation due to the
malondialdehyde are chemically highly reactive COX-2 overexpression specifically inhibits
and form adducts with DNA (48). Fas-mediated apoptosis (53). Another evidence
supporting the role of PGs in the regulation
Prostaglandins and cell proliferation of apoptotic rate of tumor cells is the studies
Previous studies have demonstrated that demonstrating that COX-2 overexpression in
PGs stimulate proliferation of different cell these cells increases their resistance to apoptosis
lines derived from gastrointestinal tract such as (54). Conversely, COX-inhibitors trigger both
colonic, intestinal, gastric and esophageal cell the mitochondrial and death receptor-mediated
lines. Therefore, it is not surprising that NSAIDs apoptotic pathways with resultant cytochrome
and selective COX-2 inhibitors as inhibitors of c release. In addition, some COX-independent
PG synthesis exert the inhibitory effect on the effects on apoptosis have been observed such as
proliferation of malignant cell lines derived inhibition of NFkB signaling via inhibition of
from gastrointestinal tract (in-vitro studies) and IkB kinase B activity and through binding to the
on tumor growth in-vivo. Studying downstream nuclear receptors PPAR (55).
mechanisms can also support the role of COX-2
in carcinogenesis (15, 49). Prostaglandins and increased invasiveness
PG E2 concentration is increased in cells Tumor cell invasion is an extremely important
with COX-2 overexpression, and is considered factor for the formation of solid tumors and
as the most important downstream effector of necessary for their spread to distant organs. Matrix
COX-2. Activation of the epidermal growth degradation and cell motility are essential in this
factor receptor (EGFR) via PG E2 action is process. Matrix metalloproteinases (MMPs) are
of great interest since EGFR is recognized as a family of matrix degradation enzymes. Their
a therapeutic target in the cancer setting and expression is associated with tumor cell invasion
several EGFR inhibitors have been developed. of the basement membrane and stroma, blood

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Figure 7. Different mechanisms through which the COX-2-derived prostaglandins are involved in the carcinogenesis (derived
from (15)).

vessel penetration and metastasis (42). (TNFα), platelet derived growth factor (PDGF)
It has been demonstrated that COX-2 induces and COX-derived PGs such as PGE2 and PGI2.
MMP expression in human colon cancer cells The link between the COX-2-derived PGs
and therefore promotes metastasis (56). COX- and angiogenesis is suggested through studies
2-derived PGs play an important role in the showing a correlation between COX-2 gene
increased invasiveness of cancer cells. One of expression and angiogenesis in premalignant
the important mechanisms through which coxibs tissues and cancer. PGE2 stimulates angiogenesis
suppress the tumor invasiveness is the inhibition via the transcription factor hypoxia inducible
of matrix metalloproteinases (MMP-2 and MM- factor-1 (HIF-1 alpha) leading to the induction
9) which are known to facilitate cell invasion of VEGF. On the other hand, VEGF stimulates
and migration with degrading the extracellular the COX-2 expression. The ability of COX-2
matrix (15). and VEGF to influence each other suggests a
positive feedback amplification mechanism.
Prostaglandins and angiogenesis While mature blood vessels express COX-
Angiogenesis, the formation of new blood 1, new angiogenic endothelial cells express the
vessels from pre-existing vasculature, is an inducible COX-2. Based on these observations,
essential process in the carcinogenesis and it is hypothesized that tumor-derived growth
metastasis. Neovascularization is regulated by factors promote angiogenesis by inducing the
the balance between pro-angiogenic factors production of COX-2-derived PGE2 (15, 42).
and angiogenesis inhibitors in the local tissue
environment. Important pro-angiogenic factors Prostaglandins and immune response
include vascular endothelial growth factor PGs have ability to regulate the immune
(VEGF), basic fibroblast growth factor (bFGF), system. This is of great clinical importance
interleukin-8, tumor necrosis factor alpha since immunosuppression correlates with

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the progression of the neoplastic diseases. COX-2 and neurological diseases

Macrophages are activated and produce PG E2 COX-2 in CNS may have an ambivalent
which in turn inhibits the production of regulatory functionality since the basal production of PGs
cytokines, the B and T-cell proliferation, and through COX-2 may participate in neuronal
decreases the cytotoxic activity of natural killer homeostasis, whereas the expression of COX-2
(NK) cells. Interestingly, the induction of IL-10 is associated with brain development.
and its immunosuppressive effects are related to
PG E2 production. Thus, the overproduction of Alzheimer’s disease
COX-2-derived PGs could result in the inhibition Alzheimer’s disease (AD) is among the most
of cell-mediated antitumor response (57). important health care problems worldwide.
The neuropathological features of Alzheimer’s
Multidrug resistance disease (AD) include the accumulation of
MDR-1 (or P-glycoprotein), is an efflux microglia around plaques, a local cytokine-
pump for chemotherapeutic drugs and mediated acute-phase response, and activation
thereby contributes to multidrug resistance. of the complement cascade. This inflammatory
Overexpression of COX-2 has been found to response may damage neurons and exacerbate
increase the production and function of MDR-1 the pathological processes underlying the
in cells in culture, an effect that was prevented disease. A large number of epidemiological
by treatment with a selective COX-2 inhibitor. studies have indicated that the use of NSAIDs
Although much work is required to establish may prevent or delay the clinical features of
the clinical significance of this interaction, it AD. Since COX-2 expression in the brain
is appealing to speculate that selective COX-2 and PGE2 content in the cerebrospinal fluid
inhibitors will enhance the anti-tumor activity of have been reported to be elevated in AD
cancer chemotherapy by reducing the multidrug together with the finding that COX-2 protein
resistance (58). levels in the brain correlate with the severity
of amyloidosis and clinical dementia, it has
Aromatase activity been suggested that COX-2 inhibition by
Estrogen deprivation is an effective therapy NSAIDs might be involved in the apparent
for the prevention and treatment of hormone- protection in this setting. However, the results
dependent breast cancer. The final step in of a recent randomized, double-blind clinical
estrogen biosynthesis is catalyzed by aromatase. trial of rofecoxib vs. naproxen have failed to
PGE2 increases the aromatase activity in demonstrate a significant slowing of cognitive
cells in culture and, thus, should stimulate decline in patients with mild-to-moderate
cell proliferation indirectly by increasing Alzheimer’s disease over 12 months. Several
the estrogen biosynthesis. This implies that factors might have contributed to the failure of
inhibiting the production of estrogen in breast this trial. In particular, the selection of patients
tissue using a selective COX-2 inhibitor might with advanced neuropathology and the short
be useful for either preventing or treating breast period of exposure to treatment may have
cancer (15). played a role. Alternatively, COX-independent
It can be concluded that: 1) COX-2-derived mechanisms of NSAIDs may have contributed
PGs play a key role in the tumorogenesis; 2) The to the apparent protection demonstrated in
tumor-promoting effect of PGs may be attributed epidemiological studies. It has been reported
to their ability to stimulate the cell proliferation that NSAIDs may activate the peroxisome
and migration, to inhibit the apoptosis and to proliferator-activated receptor (PPAR). In fact,
increase angiogenesis and invasiveness; 3) PPARγ activation leads to the inhibition of
in accordance to the proposed major role of microglial expression of a broad range of pro-
COX-2 in cancerogenesis, selective COX-2 inflammatory molecules. However, it should
inhibitors have been shown in numerous studies be pointed out that no evidence is available
to exhibit strong chemopreventive effect on the to correlate these alternative mechanisms of
development of cancers. NSAIDs with their clinical benefit reported in

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COOH COOH
MeO

Naproxen buprofen

COOH COOH

NH
O Cl Cl
Ketoprofen

Diclofenac
COOH
COOH
NH MeO

N
O
Mefenamic acid

Cl
COOH
Indomethacin
F

O
O
S
N
H
N N

MeOS OH O
Sulindac
Piroxicam

Figure 8. NSAIDs.

population-based studies. anticipated, therefore, that NSAIDs 1 rather than

COX-2 is constitutively expressed at high selective COX-2 inhibitors would be more likely
levels in brain and is specifically concentrated to reduce the brain inflammation selectively (41,
in pyramidal neurons which are vulnerable to 59, 60).
AD pathology. On the other hand, COX-1 is
not constitutively expressed in brain at high Parkinson disease
levels but is upregulated in reactive microglia, It has been shown that NSAIDs reduce the
the target for inflammatory suppression. So dopaminergic neuron degeneration in animal
far, COX-2 has not been detected in astrocytes models of Parkinson disease (PD), but no
and microglia in AD and is barely induced with epidemiological data are available on NSAID
the inflammatory mediators in AD. It would be use and the risk of PD. However, it has been

666
 Selective COX-2 Inhibitors: A Review of Their Structure-Activity

shown that COX-2 is up-regulated in brain bicyclic and tricyclic fused and spiro ring systems
dopaminergic neurons of both PD postmortem have frequently been used as the central core for
specimens and 1-methyl-4-phenyl-1,2,3,6- this group of compounds.
tertrahydropyridine (MPTP) mouse model
of PD, and COX-2 inhibition prevents the a) 4-membered cores
formation of the oxidant species dopamine- Ring contraction to smaller carbocycles
quinone involved in the pathogenesis of PD, such as cyclobutenes also leads to potent
suggesting that the inhibition of COX-2 may COX-2 inhibitors as well as insertion of 5- and
be a valuable target for the development of 6-membered carbocyclic or heterocyclic groups
new therapies for PD aimed at slowing the (Figure 10). Compounds with a cyclobutene
progression of the neurodegenerative process central ring show IC50-values for COX-1 of 0.12
(61). [1] and > 5 mmol [2], for COX-2, 0.002 [1] and
0.11[2] μM (63).
COX-2 inhibitors
Within the last two decades, the volume of b) 5-membered cores
literature on the structural types introduced as A wide variety of 5-membered heterocycles
selective COX-2 inhibitors is enormous. In this can serve as a template for COX-2 inhibitors
review, we have chosen to focus on the structure- (Figure 13), i.e. pyrrole [3] (64), pyrazole
activity relationship (SAR) and also various (celecoxib, [4], [5]) (65), (62), thiazole [6] (66),
structural families of compounds, which have oxazole [7], [8] (67), oxadiazole [9] (68), furanone
emerged within the last years. The chemical (rofecoxib, [10]) (69, 70), imidazole [11], [12]
structures of COX-2 inhibitors are heterogenic (71,72), isoxazole (valdecoxib), triazole [13] (73)
so that a further classification of this group will and thiophene (DuP 697).
be made in the following chapter. Contrary to Knaus et al. reported a series of
the classic NSAIDs (Figure 8), this new class of methanesulfonamide analogues of rofecoxib
enzyme inhibitors is lacking a carboxylic group, which in general, show decreased COX-2
thus effecting COX-2 affinity by a different inhibitory potency and selectivity in comparison
orientation within the enzyme without formation with rofecoxib. Compound [10] was the most
of a salt bridge in the hydrophobic channel of promising analogue among the synthesized
the enzyme. analogues (COX-2, IC50 = 0.9 μM; SI > 111).
In general classification, selective COX- Zarghi et al. reported a novel series of
2 inhibitors belong to two major structural 2,3-diaryl-1,3-thiazolidine-4-ones possessing a
classes: 1) Tricyclics (also known as ortho-diaryl SO2Me pharmacophore at the para-position of
heterocycles or carbocycles); 2) Non-tricyclics. C-2 phenyl ring in conjunction with a substituent
(H, F, Cl, Me and OMe) at the para-position of
Tricyclics the N-3 phenyl ring. Compounds [14] and [15]
All of the compounds in this class possess were potent COX-2 inhibitors which showed
1,2-diarylsubstitution on a central hetero or higher selectivity than celecoxib (74). Besides,
carbocyclic ring system with a characteristic a group of 2-aryl, 3-benzyl-(1,3-oxazolidine or
methanesulfonyl, sulfonamido, azido, 1,3-thiazolidine)-4-ones possessing a SO2Me
methanesulfonamide or pharmacophore-based pharmacophore at the para-position of C-2 phenyl
tetrazole group on one of the aryl rings that plays ring were reported by Zarghi et al. Compound [16]
a crucial role on COX-2 selectivity. Coxibs such (COX-2, IC50 = 0.21 μM; SI > 476), has a higher
as Celecoxib, Rofecoxib, Valdecoxib and etc, selectivity index than celecoxib. Compound [17]
belong to this common structural class (62) has lower potency and selectivity (COX-2, IC50 =
(Figure 9). 0.32 μM; SI > 312.5), which suggests that COX-
Compounds belonging to this class can be 1/-2 inhibition in this scaffold is sensitive to the
sub-classified based on the size and type of the type of heteroatom (O, S) (75) (Figure11).
central heterocyclic or carbocyclic ring system New series of 2,4,5-triarylimidazoles
(core). 4-, 5- and 6-membered rings and also possessing a SO2CH3 pharmacophore at the

667
Zarghi A and Arfaei S / IJPR (2011), 10 (4): 655-683

H2NO2S
O

N N O
CF3

H3CO2S
H3C
Rofecoxib
Celecoxib

H3CO2S H3CO2S

Br O
S N

F
DuP-697 Valdecoxib

H3CO2S

Cl

H3C N

Etoricoxib

Figure 9. Coxibs.

para position of C-4 phenyl ring has also been shown good COX-2 inhibitory potencies and
reported by Zarghi et al. selectivities (77) (Figure 13).
Structure-activity relationship of this group Li et al. described the SAR studies on a new
showed that COX-2 inhibitory potency and class of orally active COX-2 inhibitors based
selectivity is dependent on the nature of the on the six-member heterocyclic pyridazinone
substituent on the C-2 phenyl ring. The order system. Various n-substituted analogues were
of selectivity was OH > F > OMe > H , Me > initially prepared to evaluate the effect of
NHCOMe > Cl. Compound [18] possessing OH n-substitution in this category. It was very clear
group at the para-position of the C-2 phenyl ring that n-substitution was absolutely required for a
is the most potent and selective COX-2 inhibitor good in-vitro COX-2 inhibitory potency since
in this group (76) (Figure 12). the unsubstituted analogues were not potent.
An increase in the size of nitrogen substituent
c) 6-membered cores improved COX-2 inhibitory potency. Two
One of the first structural types emerged in this potent and selective COX-2 inhibitors [20] and
category were pyridine series. 1,2-diarylpyridine [21] have been identified from the pyridazinone
derivatives (such as etoricoxib) and template. These two compounds also showed
2,3-diarylpyridine derivatives [19] have excellent efficacy in animal models of anti-

668
 Selective COX-2 Inhibitors: A Review of Their Structure-Activity

2,3-diaryl-4H-chromen-4-ones [29] (85),

2,3-diarylquinoxalines [30] (81), benzo-
O 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 14).
H3CO2S Zarghi et al. reported new 1,3-benzthiazinan-
H3CO2S 4-one derivatives possessing a sulfonylmethyl
pharmacophore at the para-position of C-2
Figure 10.
phenyl ring. In this class of compounds, COX-
1/-2 inhibition is sensitive to the nature of the
N-3 substituents, and 3-(4-fluoropheny)-2-(4-
methylsulfonylphenyl)-1,3-benzthiazinan-4-one
inflammation, the rat paw edema and rat pyresis [35] exhibited high COX-2 inhibitory potency
assays (78) (Figure 13). and selectivity (90) (Figure 15).
Pyrimidine-based COX-2 inhibitors were A new group of 4,5,6,7-tetrahydro-1H-
introduced by Orjales et al. Compound [22] was benzo[d]imidazoles possessing a SO2CH3
also the most selective pyrimidine derivative pharmacophore at the para-position of C-2
of the series with a calculated HWB selectivity phenyl ring has been reported by Zarghi et al.
index of 81,300 (780-fold higher than rofecoxib) Compound [36] possessing a fluoro atom at the
(79) (Figure 13). para-position of N-1 phenyl ring is the most
Singh et al. reported 2,3-diarylpyrazines potent and selective COX-2 inhibitor in this
having 4-methylsulfonyl/sulfonamide phenyl group (91) (Figure 15).
pharmacophore. Compounds [23] and [24] Zarghi et al. also introduced quinoline
were the most selective COX-2 inhibitors in this as the central core template for potent and
group (80). The 2,3-diarylpyrane-4-ones [25] selective COX-2 inhibitors. In a group of
and 3,4-diarylpyrane-2-ones [26] containing a 4-carboxyl quinoline derivatives possessing
para-methylsulfonyl pharmacophore have also a methylsulfonyl COX-2 pharmacophore at
shown to be the proper scaffolds for selective the para-position of the C-2 phenyl ring in
COX-2 inhibitors with potent oral anti- conjunction with various substituents at C-7
inflammatory activity (81, 82) (Figure 13). and C-8 quinoline ring, compound [37] was the
Zarghi et al. reported a group of 2,3-diaryl- most potent and selective COX-2 inhibitor, with
1,3-thiazolidine-4-ones possessing a COX-2 potency and selectivity higher than the reference
SO2Me pharmacophore at the para-position of drug, celecoxib (92).
C-2 phenyl ring in conjunction with different Furthermore, in a series of 2,3-diarylquinoline
substituents at the para-position of the N-3 derivatives, compound [38] possessing a
phenyl ring. Compound [27] was the most carboxyl group at C-4 position of the quinoline
potent and selective COX-2 inhibitor among ring, showed the highest COX- 2 inhibitory
this group of compounds. It was as potent as potency and selectivity (93). Zarghi et al. also
celecoxib (COX-2 IC50 = 0.06 μM; S.I. = 405), reported 2-(4-(substituted) phenyl)quinoline-4-
in terms of COX-2 inhibitory activity but carboxylic acid derivatives possessing benzoyl
showed less selectivity (83) (Figure 13). moiety at C-6 or C-8 position of the quinoline
ring. The rational for the design of these
d) Fused bicyclic cores compounds was based on ketoprofen structure
Apart from single 4-, 5- or 6-membered as a part of 2-aryl-quinoline-4-carboxylic acid
heterocyclic or carbocyclic rings, numerous scaffold. Compound [39] was the most selective
examples of bicyclic or fused-ring systems COX-2 inhibitor in this group (COX-2 IC50 =
as the central template have also appeared 0.077 μM; S.I. = 1298), with selectivity index of
in the literature. Indoles [28] (84), higher than the reference drug, celecoxib (COX-

669
Zarghi A and Arfaei S / IJPR (2011), 10 (4): 655-683

F H2NO2S

N N
N CF3
CH2COOEt

H3C
H3CO2S
3 Celecoxib
COX-2 IC50 = 0.04 μM COX-1 IC50 > 100 μM

H2NO2S Cl

N N N N
CF3 CF3

HO
H3C H3CO2SHN
4 5
COX-2 IC50 = 0.76 μM COX-2 IC50 = 0.03 μM
COX-1 IC50 = 278 μM COX-1 IC50 = 15.6 μM

H3CO2S F

N N
S O

H2NO2S
6 7
COX-2 IC50 = 0.029 μM COX-2 IC50 = 0.009 μM
COX-1 IC50 = 72.5 μM COX-1 IC50 = 10.5 μM

H3CO2S
O
F O
O
N

H3CO2S
8 9
COX-2 IC50 = 0.30 μM COX-2 IC50 = 0.12 μM
COX-1 IC50 > 100 μM COX-1 IC50 = 11.6 μM

670
 Selective COX-2 Inhibitors: A Review of Their Structure-Activity

O O

O O

H3CO2S H3CO2SHN
Rofecoxib 10
COX-2 IC50 = 0.90 μM COX-1 IC50 > 100 μM

Br H3CO2S
SCH3
H
N N
N CF3
N

H3CO2S F
11 12
COX-2 IC50 = 0.43 μM COX-2 IC50 = 0.20 μM
COX-1 IC50 > 25 μM COX-1 IC50 > 100 μM

H3CO2S
SEt
N
N
N

F
13
COX-2 IC50 = 0.018 μM
COX-1 IC50 = 0.0205 μM

Figure 11.

2 IC50 = 0.06 μM; S.I. = 405). Its regioisomer, contain a two-membered or three-membered
compound [40] is also a very potent and selective chain structure which is the basic point for sub-
COX-2 inhibitor in this series of compounds classification of these compounds.
(94) (Figure 16).
a) Non-tricyclics with a two-membered
Non-tricyclics central template
In addition to the classical tricyclic COX-2 The 1,2-diarylethenes such as natural
inhibitors such as Coxib family, there are several resveratrol analogues [41] (95) and also 2-alkyl-
non-classical structures which we here classify 1,2-diarylolefines [42] (96), 1,1,2-triarylethenes
as non-tricyclics. These series of compounds [43], [44], [45] (97-99), acetylenes [46] (100),
lack the cyclic central core. Instead, they phenylazobenzenesulfonamides [47] (101) and
possess acyclic central systems such as olefinic, 4-phenyliminoethyl benzenesulfonamides [48]
iminic, azo, acetylenic and α,β-unsaturated (102) are included in this group (Figure 17).
ketone structures. The central acyclic core may Knaus et al. introduced series of triaryl (Z)-

671
Zarghi A and Arfaei S / IJPR (2011), 10 (4): 655-683

H3CO2S H3CO2S

X
S
N
N
O
O
R
14 16
R = F; COX-2 IC50 = 0.12 μM X=O; COX-2 IC50 = 0.21 μM
COX-1 IC50 > 100 μM COX-1IC50 > 100μM
COX-2 SI > 833 COX-2 SI > 476

15 17
R=OMe; COX-2 IC50 = 0.16 μM X=S; COX-2 IC50 = 0.32 μM
COX-1 IC50 > 100 μM COX-1 IC50 > 100 μM
COX-2 SI > 625 COX-2 SI > 312.5

H3CO2S

N
OH
N
H
18
COX-2 IC50 = 0.15 μM
COX-1 IC50 = 11.25 μM
COX-2 SI 75

Figure 12.

olefins, in which COX-2 inhibitory potency or ortho-position of the C-1 phenyl ring on a
and selectivity increased considerably with the linear acetylene template. The SAR data show
increase in 2-alkyl chain length (up to 4 carbons). that the isozyme selectivity in these compounds
N-Butyl substituted compound [43] exhibited is dependent on the position of SO2Me group
excellent potency and selectivity better than on C-1 phenyl ring, as well as the nature of
celecoxib. In addition, in series of 2-alkyl-1,1,2- the substituent on C-2 phenyl ring. Compound
triaryl (Z)-olefins possessing para-MeSO2NH/ [46] was the most potent and selective COX-2
N3 as COX-2 pharmacophoric feature on the inhibitor among these compounds.
C-1 phenyl ring, compound [44] was the best,
exhibiting potency comparable to celecoxib. In b) Non-tricyclics with a three-membered
series of 1,1,2-triaryl (E)-ethenes having para- central template
methylsulfonyl moiety on the C-1 phenyl ring, Chalcone derivatives are one of the
substitution at the C-2 phenyl ring with 4-fluoro most important groups of compounds in
substituent afforded [45] with better inhibitory this category. Zarghi et al. for the first time
potency and selectivity than celecoxib (Figure reported a group of (E)-1,3-diarylprop-2-
17). en-1-one regioisomers possessing a COX-2
Knaus et al. reported a group of SO2Me pharmacophore at the para-position of
1-((methylsulfonyl)phenyl)-2-phenylacetylene C-1 or C-3 phenyl ring in conjunction with a
regioisomers in which the COX-2 SO2Me substituent (H, Me, F, and OMe) at the para-
pharmacophore was located at the para-, meta- position of the other phenyl ring. SAR studies

672
 Selective COX-2 Inhibitors: A Review of Their Structure-Activity

H3CO2S SO2CH3

Cl
F
N

H3C N
F3C N OMe
Etoricoxib 19
SO2CH3 SO2CH3

N N
N N
O
O O
F
20 21
COX-2 IC50 (HWB assay) = 1.7 μM COX-2 IC50 (HWB assay) = 0.3 μM
COX-1 IC50 > 10 μM COX-1 IC50 = 3 μM

Cl SO2NH2

N N

N N N
H
S
SO2CH3 F
22 23
COX-2 IC50 (HWB assay) = 1.2 nM COX-2 IC50 = 1.07 μM
SI > 81300 COX-1 IC50 > 300 μM
F
SO2NH2

N
O F
O
N
O
OCH3
SO2CH3
24 25
COX-2 IC50 = 0.46 μM COX-2 IC50 = 0.08 μM
COX-1 IC50 = 97 μM COX-1 IC50 = 22.3 μM

SO2CH3
O

O O

EtO S

SO2CH3
26 27
COX-2 IC50 0.05 μM COX-2 IC50 0.06 μM
COX-1 IC50 > 100 μM COX-1 IC50 17.15 μM

Figure 13.

673
Zarghi A and Arfaei S / IJPR (2011), 10 (4): 655-683

F
O

SO2NH2 O
N
H SO2CH3
28 29
COX-2 IC50 = 0.09 μM COX-2 IC50 = 0.03 μM
COX-1 IC50 > 10 μM COX-1 IC50 < 5% inhibition at 10 μg/mL

SO2CH3 F

N
O O
N
O
OCH3 SO2CH3
30 31
COX-2 IC50 = 0.40 μM COX-2 IC50 (HWB assay) = 1.0 μM
COX-1 IC50 > 30 μM COX-1 IC50 (HWB assay) 20 μM

SO2CH3 F

OEt N
SO2CH3
N N
N N
N
32 33
COX-2 IC50 = 0.003 μM COX-2 IC50 = 0.60 μM
COX-1 IC50 > 84.2 μM COX-1 IC50 =13 μM
H
N O

O2N
N N

H2NO2S
34
COX-2 IC50 = 0.24 μM
COX-1 IC50 = 4.7 μM

Figure 14.

showed that the presence of SO2Me on C-1 were introduced afterwards (104) (Figure 18).
phenyl ring results in better COX-2 inhibitory In the continuation of this research, Zarghi et
potency and selectivity. Compound [49] was al. also described the synthesis and biological
the most potent and selective COX-2 inhibitor evaluation of a group of acyclic (E) and (Z)-
in this group (103). Compounds possessing N3 1,2,3-triaryl-2-propen-1-ones possessing a
and NHSO2Me pharmacophores, [50] and [51], methylsulfonyl COX-2 pharmacophore at

674
 Selective COX-2 Inhibitors: A Review of Their Structure-Activity

F N
O SO2CH3
N
N

SO2CH3
35 36
F
COX-2 IC50 = 0.05 μM COX-2 IC50 = 0.34 μM
COX-1 IC50 = 12.95 μM COX-1 IC50 = 55.7 μM
COX-2 SI = 259.0 COX-2 SI = 163.8

Figure 15.

the para-position of the C-1 phenyl ring in potent and selective inhibitors of the COX-2
conjunction with various aryl substituents isozyme. (Z)-1-(4-(methylsulfonyl) phenyl)-
at C-3 propenone moiety. In these designed 2,3-diphenylprop-2-en-1-one [52] showed
compounds, we utilized prop-2-en-1-one the most potency and selectivity on COX-2
scaffold instead of olefin moiety in 1,1,2-triaryl inhibition (105) (Figure 18).
olefins. The SAR studies indicated that in this A group of 1,3-diarylurea derivatives
class of compounds, COX-1/-2 inhibition is possessing a methylsulfonyl pharmacophore at
sensitive to the geometry of propenone and the the para-position of the N-1 phenyl ring having
type of substituent at the C-3 of the propenone a variety of substituents (H, F, Cl, Me, OMe) at
moiety. The Z isomers appeared to be more the para-position of the N-3 phenyl ring were

COOH

SO2CH3
37 38
COX-2 IC50 = 0.043 μM COX-2 IC50 = 0.07 μM
COX-1 IC50 = 22.1 μM COX-1 IC50 = 48.1 μM
COX-2 SI = 513.9 COX-2 SI = 687.1

O COOH COOH

N N

N3 O N3
39 40
COX-2 IC50 = 0.077 μM COX-2 IC50 = 0.057 μM
COX-1 IC50 > 100 μM COX-1 IC50 = 65.55 μM
COX-2 SI = 1298.7 COX-2 SI = 1150

Figure 16.

675
Zarghi A and Arfaei S / IJPR (2011), 10 (4): 655-683

OH
HO

OH
n-C6H13
SO2CH3

OH
41 42
COX-2 IC50 = 0.0113 μM COX-2 IC50 = 0.77 μM
COX-1 IC50 = 4.713 μM COX-1 IC50 > 100 μM

SO2CH3

H3CO2SHN

n-C6H13
n-C4H9

43 44
COX-2 IC50 = 0.014 μM COX-2 IC50 = 0.03 μM
COX-1 IC50 > 100 μM COX-1 IC50 > 100 μM

SO2CH3

H3C

SO2CH3
45 46
COX-2 IC50 = 0.0316 μM COX-2 IC50 = 0.32 μM
COX-1 IC50 > 100 μM COX-1 IC50 > 100 μM

H2NO2S H2NO2S

N N
N

MeS NH2 N

47 48
COX-2 IC50 = 2.04 μM (HWB assay) COX-2 IC50 = 1.95 μM (HWB assay)
COX-1 IC50 = 23.28 μM (HWB assay) COX-1 IC50 = 64.42 μM (HWB assay)

Figure 17.

676
 Selective COX-2 Inhibitors: A Review of Their Structure-Activity

O O

H3CO2S CH3 N3 CH3

49 50
COX-2 IC50 = 0.3 μM COX-2 IC50 = 1.0 μM
COX-1 IC50 = 32 μM COX-1 IC50 > 100 μM

O O

N3 CH3 H3CO2S

51 52
COX-2 IC50 = 0.3 μM COX-2 IC50 = 0.07 μM
COX-1 IC50 > 22.2 μM COX-1 IC50 = 14.27 μM

H H
N N

O
H3CO2S OCH3
53
COX-2 IC50 = 0.11 μM
COX-1 IC50 = 22.4 μM

Figure 18.

also reported by Zarghi et al. The SAR results 2 over COX-1 (108) (Figure 19). Amongst
showed that the presence of a hydrogen acceptor the NSAIDs studied so far, the indomethacin
group such as methoxy or fluorine substituent template appears the most flexible in delivering
at the para-position of the N-3 phenyl ring may COX-2-specific inhibitors following the
improve the selectivity and potency of COX-2 functional group manipulations. However, the
inhibition. Compound [53] was the most potent methodology utilized in NSAID modification
and selective COX-2 inhibitor in this group does not follow a general scheme. Various
(106) (Figure 18). attempts have been made to shift the enzyme
selectivity of indomethacin from COX-1 to
Modified NSAIDs COX-2 while keeping the potency on the same
Modifying well known NSAIDs into selective level and reducing the unwanted side-effects at
COX-2 inhibitors represents an interesting the same time. In principle, the strategy consisted
strategy. Indomethacin, zomeoirac [54] (107), of introducing larger substituents to fit into the
diclofenac and many other NSAIDs have active site volume of COX-2 (10).
been successfully elaborated into the selective Conversion of non-selective NSAIDs
COX-2 inhibitors. Novartis group described to esters and amides is a facile strategy for
conversion of diclofenac into lumiracoxib [55], generating COX-2 inhibitors from known drugs
which exhibits 500-fold selectivity for COX- but it has the limitation that indomethacin esters

677
Zarghi A and Arfaei S / IJPR (2011), 10 (4): 655-683

O
O
N
N
N
COOH Cl NH
Cl

Zomepirac 54 O
COOH COOH

NH NH
Cl Cl F Cl

55
Diclofenac Lumiracoxib

Figure 19.

and possibly some amides may be hydrolyzed processes such as inflammation and pain.
to indomethacin in-vivo. Therefore, indolyl Thus, it was though that more selective COX-2
esters and amides with essentially the ‘‘reverse’’ inhibitors would have reduced the side effects.
orientation have been reported that selectively Moreover, recent studies indicating the place of
inhibit COX-2. Such compounds eliminate or COX-2 inhibitors in cancer chemotherapy and
minimize the generation of indomethacin in- neurological diseases such as Parkinson and
vivo. Compounds [56] and [57] are the most Alzheimer’s diseases still continues to attract
potent and selective COX-2 inhibitors resulted investigations on the development of COX-2
from this strategy (109) (Figure 20). inhibitors. In this review, the main emphasis was
on the structure-activity relationship (SAR) and
Conclusions also various structural families of compounds,
which have emerged within the last decade. In
The development of selective COX-2 general classification, selective COX-2 inhibitors
inhibitors started in early 1990’s with the belong to two major structural classes: 1)
identification of COX-2 isoenzyme which was Tricyclics, 2) Non-tricyclics. All of the tricyclic
found to be responsible for the pathological compounds possess 1,2-diarylsubstitution on a

O O
O HN

H3CO H3CO
OCH3 Cl
N N
O

Cl Br
56 57
COX-2 IC50 = 0.04 μM COX-2 IC50 = 0.04 μM
COX-2 IC50 > 66 μM COX-2 IC50 > 66 μM

Figure 20.

678
 Selective COX-2 Inhibitors: A Review of Their Structure-Activity

central hetero or carbocyclic ring system with (13) Tazawa R, Xa XM, Wu KK and Wang LH. Biochemical
characterization of the genomic structure, chromosomal
a characteristic methanesulfonyl, sulfonamido,
location and promoter of human prostaglandin h
azido, methanesulfonamide or tetrazole synthase-2 gene. Biophys. Res. Commun. (1994) 203:
pharmacophore group on one of the aryl rings 190–199.
that plays a key role on COX-2 selectivity. (14) Williams CS and DuBois RN. Prostaglandin
Non-tricyclics lack the cyclic central core. endoperoxide synthase: why two isoforms? Am.
Instead, they possess acyclic central systems J. Physiol. (1996) 270: G393-400.
(15) Konturek PC, Kania J, Burnat G, Hahn EG and
such as olefinic, iminic, azo, acetylenic and Konturek SJ. Prostaglandins as mediators of COX-
α,β- unsaturated ketone structures. The central 2 derived carcinogenesis in gastrointestinal tract. J.
acyclic core may contain a two-membered or Physiol. Pharmacol. (2005) 56: S57-73.
three-membered chain structure. (16) Yamagata K, Andreasson KA, Kaufmann WE, Barnes
CA and Worley PF. Expression of a mitogen-inducible
cyclooxygenase in brain neurons: regulation by
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