• Biomolecules & Therapeutics
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• v.9 no.2
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• pp.69-78
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• 2001

Cyclooxygenase (COX) is an enzyme, which catalyzes the production of prostaglandins from arachi-donic acid and exists in two isoforms (COX-1 and COX-2). COX-1 is involved in the maintenance of physiological functions such as platelet aggregation, cytoprotection in the stomach and maintenance of normal kidney function. COX-2 is induced significantly in vivo under inflammatory conditions. COX-1 and COX-2 serve different physiological and pathological functions. All commercially available nonsteroidal antiinflammatory drugs (NSAIDS) are inhibitors of both COX-1 and COX-2. Therefore, selective inhibitors of COX-2 may be effective antiinflammatory agents without the ulcerogenic effects associated with current NSAms. Since the mid 1990s, a number of reports have been appeared on the preparation and biological activity of selective COX-2 inhibitors. Recently celecoxib, and rofecoxib, the representative COX-2 inhibitors, are introduced in the drug market. In this paper the relationship of structure-activity for selective COX-2 inhibitors is reviewed.

• The Korean Journal of Physiology and Pharmacology
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• v.10 no.1
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• pp.45-50
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• 2006

Melittin-induced pain model has been known to be very useful for the study of pain mechanism. Melittin-induced nociceptive responses are reported to be modulated by the changes in the activity of excitatory amino acid receptor, calcium channel, spinal serotonin receptor and extracellular signaling-regulated kinase. The present study was undertaken to investigate the role of cyclooxygenase (COX) in the melittin-induced nociception. Changes in mechanical threshold, flinchings and paw thickness were measured before and after intraplantar injection of melittin in the rat hind paw. Also studied were the effects of intraperitonealy administered diclofenac (25 mg & 50 mg/kg), piroxicam (10 mg & 20 mg/kg) and meloxicam (10 mg & 20 mg/kg) on the melittin-induced nociceptions. Intraplantar injection of melittin caused marked reduction of mechanical threshold that was dose-dependently attenuated by non-selective COX inhibitor (diclofenac) and selective COX-1 inhibitor (piroxicam), but not by COX-2 inhibitor (meloxicam). Melittin-induced flinchings were strongly suppressed by non-selective COX and COX-1 inhibitor, but not by COX-2 inhibitor. None of the COX inhibitors had inhibitory effects on melittin-induced increase of paw thickness (edema). These experimental findings suggest that COX-1 plays an important role in the melittin-induced nociceptive responses.

• Genomics & Informatics
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• v.15 no.2
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• pp.56-64
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• 2017

We have previously reported that NS-398, a cyclooxygenase-2 (COX-2)-selective inhibitor, inhibited replicative cellular senescence in human dermal fibroblasts and skin aging in hairless mice. In contrast, celecoxib, another COX-2-selective inhibitor, and aspirin, a non-selective COX inhibitor, accelerated the senescence and aging. To figure out causal factors for the senescence-modulating effect of the inhibitors, we here performed cDNA microarray experiment and subsequent Gene Set Enrichment Analysis. The data showed that several senescence-related gene sets were regulated by the inhibitor treatment. NS-398 up-regulated gene sets involved in the tumor necrosis factor ${\beta}$ receptor pathway and the fructose and mannose metabolism, whereas it down-regulated a gene set involved in protein secretion. Celecoxib up-regulated gene sets involved in G2M checkpoint and E2F targets. Aspirin up-regulated the gene set involved in protein secretion, and down-regulated gene sets involved in RNA transcription. These results suggest that COX inhibitors modulate cellular senescence by different mechanisms and will provide useful information to understand senescence-modulating mechanisms of COX inhibitors.

• The Korean Journal of Pain
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• v.23 no.4
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• pp.236-241
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• 2010

Background: Selective inhibitors of cycloosygenase (COX)-2 are commonly used analgesics in various pain conditions. Although their actions are largely thought to be mediated by the blockade of prostaglandin (PG) biosynthesis, evidences suggesting endogenous opioid peptide link in spinal antinociception of COX inhibitor have been reported. We investigated the roles of opioid receptor subtypes in the spinal antionociception of selective COX-2 inhibitor. Methods: To examine the antionociception of a selective COX-2 inhibitor, DUP-697 was delivered through an intrathecal catheter, 10 minutes before the formalin test in male Sprague-Dawley rats. Then, the effect of intrathecal pretreatment with CTOP, naltrindole and GNTI, which are ${\mu}$, $\delta$, and k opioid receptor antagonist, respectively, on the analgesia induced by DUP-697 was assessed. Results: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2 Naltrindole and GNTI attenuated the antinociceptive effect of intrathecal DUP-697 during both phases of the formalin test, CTOP reversed the antinociception of DUP-697 during phase 2, but not during phase 1, Conclusions: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. The $\delta$ and $\kappa$ opioid receptors are involved in the activity of COX-2 inhibitor on the facilitated state as well as acute pain at the spinal level, whereas the ${\mu}$ opioid receptor is related only to facilitated pain.

• The Korean Journal of Pain
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• v.24 no.4
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• pp.179-184
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• 2011

Background: The analgesic mechanisms of cyclooxygenase (COX)-2 inhibitors have been explained mainly on the basis of the inhibition of prostaglandin biosynthesis. However, several lines of evidence suggest that their analgesic effects are mediated through serotonergic or adrenergic transmissions. We investigated the roles of these neurotransmitters in the antinociception of a selective COX-2 inhibitor at the spinal level. Methods: DUP-697, a selective COX-2 inhibitor, was delivered through an intrathecal catheter to male Sprague-Dawley rats to examine its effect on the flinching responses evoked by formalin injection into the hindpaw. Subsequently, the effects of intrathecal pretreatment with dihydroergocristine, prazosin, and yohimbine, which are serotonergic, ${\alpha}1$ adrenergic and ${\alpha}2$ adrenergic receptor antagonists, respectively, on the analgesia induced by DUP-697 were assessed. Results: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2. But, intrathecal dihydroergocristine, prazosin, and yohimbine had little effect on the antinociception of intrathecal DUP-697 during both phases of the formalin test. Conclusions: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. Either the serotonergic or adrenergic transmissions might not be involved in the analgesic activity of COX-2 inhibitors at the spinal level.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.94.2-94.2
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• 2003

CJ-11668 is a new potent and selective COX-2 inhibitor. CJ-11668 showed COX-2 inhibition (IC50) of 65nM and selectivity ratio (COX-l/COX-2) of 770 in the cell based assay. In the human whole blood assay, CJ-11668 showed COX-2 inhibition (IC50) of 370nM and selectivity ratio (COX-l/COX-2), 135. The treatment of CJ-11668 (5 mg/kg, p.o) produced a significant inhibition (35%) of inflamed rat paw volume in the carrageenan-induced acute inflammation. CJ-11668 also suppressed the PGE2 level (69% inhibition, 1 mg/kg, p.o) in the zymosan-induced mouse air pouch model after 3 hrs. (omitted)

• Archives of Pharmacal Research
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• v.22 no.4
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• pp.372-379
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• 1999

A series of disubstituted 4,5-polymethylenepyrazoles were synthesized and evaluated their inhibitory activities against COX-2. Some compounds showed strong (0.3 nM) inhibitory activity on COX-2 and were found somewhat selective (up to 16) on COX-2 over COX-1.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.30 no.4
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• pp.333-344
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• 2008

The objectives of this study was to explore the growth pattern of the oral squamous cell carcinoma when overexpressed COX was inhibited, explore the pathway that COX inhibitors suppressed the proliferation of cancer cells, and then hereafter investigate the potential of COX as chemopreventive target for oral squamous cell carcinoma. For confirming the COX-dependent effect and mechanisms on growth of the oral cancer cells, we treated the nonselective NSAID, Mefenamic acid and COX-2 selective inhibitor, Celecoxib in HN4 cell line. And then the cell line was evaluated with MTT assay and growth curve, the production of PGE2, total RNA extraction and RT-PCR analysis, and TEM The results were obtained as follows: 1. After administration of medication, in the result of MTT assay, Celecoxib inoculated group inhibit the cell growth rather than Mefenamic acid inoculated group. 2. The growth curve of cell line showed as time passes by there was a dramatic cell growth in the control group, and gradual growth inhibition was found in medication inoculated group and, in Celecoxib inoculated group there was more inhibition of cell growth. 3. After the administration of medication, Celecoxib tend to inhibit the synthesis of PGE2 more than Mefenamic acid. Mefenamic acid inhibit the synthesis of PGE2 more as the concentration gets high, but Celecoxib inhibited the synthesis of PGE2 even in low concentration. 4. After the administration of medication, the revelation of COX mRNA in cell line, there was a 50% decrease in COX-1, 60% decrease in COX-2 as in $50{\mu}M$ Mefenamic acid, and in Celecoxib $50{\mu}M$ there was not much difference in COX-1 and 90% decrease in COX-2 was found. 5. HN4 cell line showed broken nucleus and tangled cytoskeleton bundles in cytoplasm which meant apoptotic features after the treatment of Celecoxib in TEM view. Depending on the above results, we estimate that the inhibition of the expression of COX-2 cause the growth suppression of the oral squamous cell carcinoma, and it get achieved through pathway of reduced PGE2 production and increased apoptosis. In addition to, because COX-2 selective inhibitor specifically act to COX-2, it is considered that COX-2 selective inhibitor has the adequate potential as chemopreventive agent for oral squamous cell carcinoma.

• YAKHAK HOEJI
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• v.51 no.5
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• pp.313-317
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• 2007

A series of luotonin A homologues and their aza-analogues were prepared and evaluated their inhibitory activities on COX-1 and 2 as well as their selectivities on COX-2. The aza-analogue of dimethylene-bridged homologue of luotonin A, 3,3'-dimethylene-2-(1',8'-naphthyrid-2'-yl)-4(3H)-quinazolinone (2b), exhibited strongest inhibitory activity against COX-1 and COX-2 dependent phase of prostaglandin $D_2$ generation in mouse bone marrow-derived mast cells in a concentration-dependent manner with an $IC_{50}$ of 39.3 and $1.89{\mu}M$, respectively. Selectivity of 2b on COX-2 over COX-1 was 21 which implied 2b can be a potential lead for the development of selective COX-2 inhibitor.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1103-1110
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• 2016

In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.