Class Of Cyclooxygenase-2 Inhibitors Research Articles

Synthesis and Biological Evaluation of Gentiopicroside Derivatives as Novel Cyclooxygenase-2 Inhibitors with Anti-Inflammatory Activity.

Nonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity. We introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment. A total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity. These gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.

Development of novel pyrazole, imidazo[1,2-b]pyrazole, and pyrazolo[1,5-a]pyrimidine derivatives as a new class of COX-2 inhibitors with immunomodulatory potential

Searching for new compounds with anti-inflammatory properties is a significant target since inflammation is a major cause of pain. A series of pyrazole, imidazopyrazolone, and pyrazolopyrimidine derivatives were designed and synthesized by reaction of 3,5-diamino-1H-pyrazole derivative with cyclic and acyclic carbonyl reagents. The structure of the newly synthesized derivatives were fully characterized using different spectroscopic data and elemental analysis, and therefore, evaluated as COX-2 inhibitors. The in vitro COX-2 activity of the tested derivatives 2–13 displayed moderate to good potency with two derivatives 8 and 13 that exhibiting high potency to COX-2 with IC50 values of 5.68 ± 0.08 and 3.37 ± 0.07 μM compared with celecoxib (IC50 = 3.60 ± 0.07 μM) and meloxicam (IC50 = 7.58 ± 0.13 μM). Furthermore, the most active pyrazolo[1,5-a]pyrimidine derivatives 8 and 13 were evaluated to measure the levels of pro-inflammatory proteins such as TNF-α and IL-6 using qRT-PCR in RAW264.7 cells, and the results showed down-regulation of two immunomodulatory proteins. Surprisingly, these derivatives 8 and 13 revealed a decrease in IL-6 level with inhibition percentages of 65.8 and 70.3%, respectively, compared with celecoxib (% = 76.8). Further, compounds 8 and 13 can regulate and suppress the TNF-α with percentage inhibition of 63.1 and 59.2% to controls, while celecoxib displayed an inhibition percentage of 72.7. The Quantum chemical calculation was conducted, and data explained the structural features crucial to the activity. The molecular docking simulation and ADMET predictions revealed that the most active derivatives have good binding affinity, possess appropriate drug-likeness properties and low toxicity profiles. Finally, compounds 8 and 13 demonstrated COX-2 inhibitors with α-TNF and IL-6 suppression capabilities as a dual-action strategy to get more effective treatment.

Abstract P4-08-11: Surface Plasmon Resonance (SPR) Analysis of COX-2 Expression for Early Detection and Progression of Breast Cancer and Evaluation of a Novel Class of Peptides as Its Inhibitor

Abstract Background: Cyclooxygenase-2 (COX-2) over expression has been observed in different cancers. Till date, COX-2 expression in breast cancer has been studied using RT-PCR and immunohistochemistry. The aim of this study was to use surface plasmon resonance (SPR) technology for determining the expression levels of COX-2 in breast cancer and design peptide inhibitors to evaluate their enzyme inhibition in vitro. Patients and methods: This case-controlled study was performed on 84 biopsy proven breast cancer patients having invasive ductal carcinoma and 40 age, sex and ethnicity matched healthy subjects. Blood and tissue samples were collected and serum and tissue lysate was prepared. Serum and tissue levels of COX-2 were evaluated using SPR where samples were allowed to flow over anti-COX-2 antibody immobilized sensor chip to obtain the respective RUs. Similarly, standard curve of COX-2 was prepared from cloned, expressed and purified protein to deduce the concentrations in different samples. To evaluate enzyme inhibition, fifteen peptides were synthesized using the solid and solution-phase peptide synthesis based on the active site structure of COX-2 and enzyme activity was evaluated spectrophotometrically. Results: A significant increase in COX-2 levels in breast cancer patients 11.23-30.77μg/ml (Mean±SD=14.55±5.74) as compared to normal controls 2.13-5.16µg/ml (Mean±SD=3.71±0.86) (P>0.0001) was observed. Serum COX-2 levels were significantly higher (P<0.0061) in patients with lymph node involvement. More than 65% patients showed significantly (P<0.0025) reduced COX-2 levels after chemotherapy. This was confirmed by western blot to check tissue level expression and spectrophotometrically to determine the activity of COX-2 at different stages. In addition, the peptides showed significant in vitro enzyme inhibition, and had a KD ranging from 1 X 10-8 to 1X10-10. Conclusion: SPR is a useful proteomic technique for early detection and monitoring progession of breast cancer and peptides are a novel class of COX-2 inhibitors that can be further developed for anti-tumor therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-11.

Nitric Oxide-Releasing Nonsteroidal Anti-Inflammatory Drugs: Gastrointestinal-Sparing Potential Drugs

The nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs in the world. Their use as anti-inflammatory, antipyretic, antithrombotic, and analgesic agents is, however, restricted by their adverse effects on gastrointestinal (GI) tract. To overcome this problem with NSAIDs, two new strategies in the development of these drugs are explained. The first approach is the development of selective inhibitors of the enzyme cyclooxygenase (COX)-2, the inducible isoform of the prostaglandin G/H synthetase enzyme. COX exists in two isoforms, viz., COX-1 and COX-2. Selective inhibitors of COX-2 will suppress prostaglandin synthesis at the sites of inflammation, but they will not interfere with the activity of COX-1, in tissues like the GI tract. The use of selective COX-2 inhibitors, however, lacks the cardioprotective effects mediated by COX-1. An alternate approach to reduce the GI toxicity of NSAIDs is the development of nitric oxide (NO)-releasing NSAIDs. It has been reported that NO does not affect the gastroduodenal mucosa and produces the same effects as endogenous prostaglandins. The present article focuses on the NO-releasing NSAIDs, which are from the conventional class of COX-2 inhibitors that have potential clinical applications, as well as some drug candidates still under development.

Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors

A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF 3 functionality. The compound SC-75416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC 50) of 0.25 μM for COX-2 and 49.6 μM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1β (IL-1β) and washed platelets the compound displayed IC 50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC 50 of 1.4 μM for lipopolysaccharide (LPS) stimulated induction of COX-2 and > 200 μM for inhibition of platelet thromboxane production. SC-75416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE 2 production with an effective dose that provides 50% inhibition (ED 50) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE 2) production with an ED 50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED 50s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED 50 of 0.081 mg/kg and an ED 80 of 0.38 mg/kg. In a model of neuropathic pain, SC-75416 had good efficacy. This compound's unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.

2, 3-Diaryl-5-ethylsulfanylmethyltetrahydrofurans as a new class of COX-2 inhibitors and cytotoxic agents

2,3-Diaryl-5-ethylsulfanylmethyltetrahydrofuran-3-ols were designed and synthesized by the allylations of benzoins followed by iodocyclization and nucleophilic replacement reactions with ethanthiol. These molecules exhibit IC(50) for COX-2 at <10 nM concentration and exhibit average GI(50) over all the 59 human tumor cell lines at microM concentration.

Synthesis and biological evaluation of 2-trifluoromethyl/sulfonamido-5,6-diaryl substituted imidazo[2,1- b]-1,3,4-thiadiazoles: A novel class of cyclooxygenase-2 inhibitors

A series of 2-trifluoromethyl/sulfonamido-5,6-diarylsubstituted imidazo[2,1- b]-1,3,4-thiadiazole derivatives 15a– j have been synthesized by the reaction of 2-amino-5-trifluoromethyl/sulfonamido-1,3,4-thiadiazoles 14a– b and appropriately substituted α-bromo-1,2-( p-substituted)diaryl-1-ethanones 13a– h. Structures of these compounds were established by IR, 1H NMR, 13C NMR, Mass, and HRMS data. The selected compounds were evaluated for their preliminary in vitro cyclooxygenase inhibitory activity against COX-2 and COX-1enzymes using colorimetric method. The compounds tested showed selective inhibitory activity toward COX-2 (80.6–49.4%) over COX-1 (30.6–8.6), amongst them compounds 15f and 15j showed appreciable COX-2 selective inhibitory activity. These compounds also exhibited significant anti-inflammatory activity (70.09–42.32%), which is comparable to that of celecoxib in the carrageenan-induced rat paw edema method.

N-Acylated sulfonamide sodium salt: A prodrug of choice for the bifunctional 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamide class of COX-2 inhibitors

Synthesis and biological evaluation of possible prodrugs of COX-2 inhibitors involving sulfonamide and hydroxymethyl groups of 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamides are described. Out of many options, the sodium salt of N-propionyl sulfonamide demonstrated much improved pharmacological profiles and physicochemical properties suitable for oral as well as parenteral administration.

Design, synthesis, and biological evaluation of 1,3-diarylprop-2-en-1-ones : A novel class of cyclooxygenase-2 inhibitors

A group of regioisomeric ( E)-1,3-diarylprop-2-en-1-one derivatives possessing a COX-2 SO 2Me pharmacophore at the para position of the C-1 or C-3 phenyl ring, in conjunction with a C-3 or C-1 phenyl (4-H) or substituted-phenyl ring (4-F, 4-OMe and 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target ( E)-1,3-diarylprop-2-en-1-ones were synthesized via a Claisen–Schmidt condensation reaction. In vitro COX-1/COX-2 isozyme inhibition structure–activity studies identified ( E)-1-(4-methanesulfonylphenyl)-3-(4-methylphenyl)prop-2-en-1-one ( 9f) as a potent COX-2 inhibitor (IC 50 = 0.3 μM) with a high COX-2 selectivity index (SI = 106) comparable to that of the reference drug rofecoxib (COX-2 IC 50 = 0.5 μM; COX-2 SI > 200). A molecular modeling study where 9f was docked in the binding site of COX-2 showed that the para-SO 2Me substituent on the C-1 phenyl ring is oriented in the vicinity of the secondary COX-2 binding site near Val523. The structure–activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design novel acyclic 1,3-diarylprop-2-en-1-ones with selective COX-2 inhibitory activity.

Design, synthesis, and biological evaluation of linear 1-(4-, 3- or 2-methylsulfonylphenyl)-2-phenylacetylenes: A novel class of cyclooxygenase-2 inhibitors

A group of regioisomeric 1-(methylsulfonylphenyl)-2-phenylacetylenes possessing a COX-2 SO 2Me pharmacophore at the para-, meta- or ortho-position of the C-1 phenyl ring, in conjunction with a C-2 phenyl or substituted-phenyl ring substituent (3-F, 3-OMe, 3-OH, 3-OAc, 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target linear 1,2-diarylacetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction followed by oxidation of the respective 1-(methylthiophenyl)-2-phenylacetylene intermediate. In vitro COX-1/COX-2 isozyme inhibition structure–activity studies identified 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene ( 12d) as a potent COX-2 inhibitor (IC 50 = 0.32 μM) with a high COX-2 selectivity index (SI > 320) comparable to the reference compound rofecoxib (COX-2 IC 50 = 0.50 μM; COX-2 SI > 200). A molecular modeling study where ( 12d) was docked in the binding site of COX-2 showed that the MeSO 2 COX-2 pharmacophore was positioned in the vicinity of the secondary COX-2 binding site near Val 523. The 1-(4-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene ( 11f, COX-1 IC 50 = 1.00 μM; COX-2 IC 50 = 0.06 μM; COX-2 SI = 16.7) and 1-(3-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene ( 12f, COX-1 IC 50 = 6.5 μM; COX-2 IC 50 = 0.05 μM; COX-2 SI = 130) regioisomers exhibited comparable COX-2 inhibition, and moderately lower selective COX-2 selectivity, relative to the reference drug celecoxib (COX-1 IC 50 = 33.1 μM; COX-2 IC 50 = 0.07 μM; COX-2 SI = 472). The most potent anti-inflammatory agent 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene ( 12d) exhibited moderate oral anti-inflammatory activity (ED 50 = 129 mg/kg) at 3 h postdrug administration relative to the reference drug celecoxib (ED 50 = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. The structure–activity data acquired indicate that the acetylene moiety constitutes a suitable scaffold (template) to design novel acyclic 1,2-diarylacetylenes with selective COX-2, or dual COX-1/COX-2, inhibitory activities.

Is COX-2 a perpetrator or a protector? Selective COX-2 inhibitors remain controversial1

COX-2(cyclooxygenase-2) has sparked a surge in pharmaceutical interest since its discovery at the beginning of the 1990s. Several COX-2 selective inhibitors that avoid gastrointestinal side effects have been successfully launched into the market in recent years. The first selective COX-2 inhibitor, celecoxib, entered the market in December 1998 [corrected] However, there are a few organs that physiologically and functionally express COX-2, particularly the glomeruli of the kidney and the cortex of the brain. Inhibition of COX-2 expression in these organs possibly causes heart attack and stroke in long-term COX-2 inhibitor users. Recently, a USA Food and Drug Agency (FDA) advisory panel re-evaluated COX-2 inhibitors and unanimously concluded that the entire class of COX-2 inhibitors increase the risk of cardiovascular problems. Thus the use of COX-2 inhibitors is still controversial, and there is a challenge for not only pharmacologists, but also the pharmaceutical industry, to develop improved painkilling and anti-inflammatory drugs. This may involve exploring a new generation of COX-2 inhibitors with different inhibitory mechanisms through computer-aided design, screening different sources of inhibitors with lower selectivity, or seeking completely new targets. Synthetic COX-2 inhibitors have high selectivity and the advantage of irreversible inhibition, whereas naturally derived COX-2 inhibitors have lower selectivity and fewer side effects, with the medical effects in general not being as striking as those achieved using synthetic inhibitors. This review discusses the mechanism of COX-2 inhibitor therapy and a possible new way of exploration in the development of anti-inflammatory, analgetic, and antipyretic drugs.

Marketing Scholars’ Roles in the Policy Arena: An Opportunity for Discourse on Direct-to-Consumer Advertising

Paul W. Farris is Landmark Communications Professor of Business, Darden Graduate School of Business Administration, University of Virginia (e-mail: farrisp@darden.virginia.edu). William L. Wilkie is Nathe Professor of Marketing, University of Notre Dame (e-mail: wwilkie@nd.edu). A Brief Background Direct-to-consumer (DTC) advertising of prescription drugs is clearly among the most significant marketing phenomena of the past decade in the United States. It is important partly because of the large amounts of money involved and its prominence in the popular media and surely because it potentially affects the length and quality of the lives of millions of people. Moreover, DTC advertising is a phenomenon that owes its existence to public policy choices in the United States and in New Zealand, and not anywhere else in the world (and in this sense, it represents an important natural experiment). In the United States, a series of regulatory actions during the 1980s and 1990s increasingly loosened restraints on the provision of information to consumers regarding ethical drugs, and advertising in this area occurred at lower levels of spending (for an informative regulatory history, see Pines 1999). In 1997, the Food and Drug Administration (FDA) issued a draft guide for firms that, in effect, allowed television advertising, and after addressing many enforcement actions to clarify the nature of such commercials, it issued final guides in 1999. At this point, the rate of spending on DTC advertising began to soar, to the extent that it is now the third largest advertising spending category, behind only automobiles and fast foods. Furthermore, as of early 2005, the attention on this topic has heightened, as unforeseen and previously undisclosed health risks have begun to surface with popular drugs such as Vioxx, Bextra, and, possibly, the entire class of Cox-2 inhibitors.

Cardiovascular Risks of Cyclooxygenase-2 Inhibitors: Where We Stand Now

The authors believe that cyclooxygenase-2 (COX-2) inhibitors, in particular at higher dosages and for longer-term use, should not be a first-line therapy for patients who can tolerate alternative t...

In vitro structure-activity relationship and in vivo studies for a novel class of cyclooxygenase-2 inhibitors: 5-aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives.

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.

Chemistry and pharmacokinetics of diarylthiophenes and terphenyls as selective COX-2 inhibitors

DuP697, 2-bromo-4-(4′-sulfonylmethyl)phenyl-5-(4′-fluoro)phenylthiophene, is a selective type 2 cyclooxygenase (COX-2) inhibitor. Its relatively weak COX-2 selectivity coupled with a poor human pharmacokinetic profile led us to seek improvements on the in vitro selectivity while at the same time, addressing some of its pharmacokinetic liabilities. In this paper we discuss some strategies at solving the PK issue within a class of COX-2 inhibitors. The result of these efforts led to the discovery of a new class of COX-2 inhibitors the terphenyls, which prove to be superior alternatives to the diarylthiophenes.