Pain is a serious subjective experience, which, although it has a protective nature, it physically and mentally exhausts the patient. The pharmacological field of development and research in the treatment and relief of pain has been dynamic and interesting ever since the isolation of salicylic acid. After discovering the molecular nature of cyclooxygenase and its inhibition, research focused on selective COX-2 inhibitors, but they were a big disappointment. Today, the possibility of contributing to safe and effective analgesic-antiphlogistic treatment for the patient with a combination of drugs is emerging again.
- Klíčová slova
- coxibs, cyclooxygenase inhibition, non-steroidal anti-inflammatory drugs,
- MeSH
- antiflogistika nesteroidní * farmakologie terapeutické užití MeSH
- bolest farmakoterapie MeSH
- cyklooxygenasa 2 MeSH
- inhibitory cyklooxygenasy 2 * terapeutické užití farmakologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika nesteroidní * MeSH
- cyklooxygenasa 2 MeSH
- inhibitory cyklooxygenasy 2 * MeSH
Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9-252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.
- Klíčová slova
- cyclooxygenase, cytotoxicity, docking, platelets, selectivity,
- MeSH
- antiflogistika nesteroidní * farmakologie MeSH
- cyklooxygenasa 2 metabolismus MeSH
- inhibitory cyklooxygenasy 2 * farmakologie chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika nesteroidní * MeSH
- cyklooxygenasa 2 MeSH
- inhibitory cyklooxygenasy 2 * MeSH
- mofezolac MeSH Prohlížeč
- SC 560 MeSH Prohlížeč
Prostaglandins and inhibitors of their synthesis (cyclooxygenase (COX) inhibitors, non-steroidal anti-inflammatory drugs) were shown to play a significant role in the regulation of hematopoiesis. Partly due to their hematopoiesis-modulating effects, both prostaglandins and COX inhibitors were reported to act positively in radiation-exposed mammalian organisms at various pre- and post-irradiation therapeutical settings. Experimental efforts were targeted at finding pharmacological procedures leading to optimization of therapeutical outcomes by minimizing undesirable side effects of the treatments. Progress in these efforts was obtained after discovery of selective inhibitors of inducible selective cyclooxygenase-2 (COX-2) inhibitors. Recent studies have been able to suggest the possibility to find combined therapeutical approaches utilizing joint administration of prostaglandins and inhibitors of their synthesis at optimized timing and dosing of the drugs which could be incorporated into the therapy of patients with acute radiation syndrome.
- Klíčová slova
- acute radiation syndrome, cyclooxygenase, gastrointestinal system, hematopoiesis, inhibitors of prostaglandin synthesis, prostaglandins,
- MeSH
- akutní radiační syndrom krev farmakoterapie etiologie metabolismus MeSH
- cyklooxygenasa 1 metabolismus MeSH
- cyklooxygenasa 2 metabolismus MeSH
- hematopoéza účinky léků MeSH
- inhibitory cyklooxygenasy 2 farmakologie terapeutické užití MeSH
- lidé MeSH
- metabolické sítě a dráhy účinky léků MeSH
- modely nemocí na zvířatech MeSH
- prostaglandiny biosyntéza farmakologie MeSH
- radioprotektivní látky farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- cyklooxygenasa 1 MeSH
- cyklooxygenasa 2 MeSH
- inhibitory cyklooxygenasy 2 MeSH
- prostaglandiny MeSH
- radioprotektivní látky MeSH
Stilbenoids represent a large group of bioactive compounds, which occur in food and medicinal plants. Twenty-five stilbenoids were screened in vitro for their ability to inhibit COX-1, COX-2 and 5-LOX. Piceatannol and pinostilbene showed activity comparable to the zileuton and ibuprofen, respectively. The anti-inflammatory potential of stilbenoids was further evaluated using THP-1 human monocytic leukemia cell line. Tests of the cytotoxicity on the THP-1 and HCT116 cell lines showed very low toxic effects. The tested stilbenoids were evaluated for their ability to attenuate the LPS-stimulated activation of NF-κB/AP-1. Most of the tested substances reduced the activity of NF-κB/AP-1 and later attenuated the expression of TNF-α. The effects of selected stilbenoids were further investigated on inflammatory signaling pathways. Non-prenylated stilbenoids regulated attenuation of NF-ĸB/AP-1 activity upstream by inhibiting the phosphorylation of MAPKs. A docking study used to in silico analyze the tested compounds confirmed their interaction with NF-ĸB, COX-2 and 5-LOX.
- Klíčová slova
- Anti-inflammatory, Cyclooxygenase, Lipoxygenase, Macrophages, Molecular docking simulations, NF-κB, Stilbenes,
- MeSH
- antiflogistika nesteroidní chemie farmakologie MeSH
- HCT116 buňky MeSH
- inhibitory cyklooxygenasy 2 chemie farmakologie MeSH
- inhibitory lipoxygenas chemie farmakologie MeSH
- lidé MeSH
- lipopolysacharidy farmakologie MeSH
- makrofágy účinky léků metabolismus MeSH
- NF-kappa B metabolismus MeSH
- preklinické hodnocení léčiv metody MeSH
- prenylace MeSH
- signální transdukce účinky léků MeSH
- simulace molekulového dockingu MeSH
- stilbeny chemie farmakologie MeSH
- TNF-alfa metabolismus MeSH
- transkripční faktor AP-1 metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 3,3',4,5'-tetrahydroxystilbene MeSH Prohlížeč
- antiflogistika nesteroidní MeSH
- inhibitory cyklooxygenasy 2 MeSH
- inhibitory lipoxygenas MeSH
- lipopolysacharidy MeSH
- NF-kappa B MeSH
- pinostilbene MeSH Prohlížeč
- stilbeny MeSH
- TNF-alfa MeSH
- transkripční faktor AP-1 MeSH
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1β and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 μM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.
- Klíčová slova
- 15-lipoxygenase, Acetylcholinesterase, Alzheimer's disease, Butyrylcholinesterase, Cyclooxygenase-2,
- MeSH
- acetylcholin nedostatek MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- buněčné linie MeSH
- buňky PC12 MeSH
- cholinesterasové inhibitory chemie MeSH
- inhibitory cyklooxygenasy 2 chemie MeSH
- inhibitory lipoxygenas chemie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- myši MeSH
- neurony účinky léků enzymologie patologie MeSH
- racionální návrh léčiv MeSH
- semikarbazidy chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- triazoly chemie farmakologie MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholin MeSH
- cholinesterasové inhibitory MeSH
- inhibitory cyklooxygenasy 2 MeSH
- inhibitory lipoxygenas MeSH
- semikarbazidy MeSH
- thiosemicarbazide MeSH Prohlížeč
- triazoly MeSH
A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a-l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1 H NMR, DEPT-Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)-1, COX-2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX-2 rather than COX-1, and the IC50 values (0.25-1.7 µM) were lower than that of indomethacin (IC50 = 9.47 µM) and somewhat higher than that of celecoxib (IC50 = 0.071 µM). The selectivity index for COX-2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC50 values of 0.02-74.03 µM, while the IC50 of the reference zileuton was 0.83 µM. The most active compound 4c (4-chlorobenzoxazole derivative) was found to have dual COX-2/LOX activity. All the synthesized compounds were docked inside the active site of the COX-2 and LOX enzymes. They linked to COX-2 through the N atom of the azole scaffold, while CO of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.
- Klíčová slova
- anti-inflammatory, cytotoxicity, diaryl imidazolone derivatives, molecular docking study,
- MeSH
- antiflogistika nesteroidní chemická syntéza chemie farmakologie MeSH
- arachidonát-5-lipoxygenasa metabolismus MeSH
- cyklooxygenasa 2 metabolismus MeSH
- imidazoly chemická syntéza chemie farmakologie MeSH
- inhibitory cyklooxygenasy 2 chemická syntéza chemie farmakologie MeSH
- inhibitory lipoxygenas chemická syntéza chemie farmakologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- racionální návrh léčiv * MeSH
- simulace molekulového dockingu MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiflogistika nesteroidní MeSH
- arachidonát-5-lipoxygenasa MeSH
- cyklooxygenasa 2 MeSH
- imidazoly MeSH
- inhibitory cyklooxygenasy 2 MeSH
- inhibitory lipoxygenas MeSH
OBJECTIVES: Chondroitin sulfate 800 mg/day (CS) pharmaceutical-grade in the management of symptomatic knee osteoarthritis consistent with the European Medicines Agency guideline. METHODS: A prospective, randomised, 6-month, 3-arm, double-blind, double-dummy, placebo and celecoxib (200 mg/day)-controlled trial assessing changes in pain on a Visual Analogue Scale (VAS) and in the Lequesne Index (LI) as coprimary endpoints. Minimal-Clinically Important Improvement (MCII), Patient-Acceptable Symptoms State (PASS) were used as secondary endpoints. RESULTS: 604 patients (knee osteoarthritis) diagnosed according to American College of Rheumalogy (ACR) criteria, recruited in five European countries and followed for 182 days. CS and celecoxib showed a greater significant reduction in pain and LI than placebo. In the intention-to-treat (ITT) population, pain reduction in VAS at day 182 in the CS group (-42.6 mm) and in celecoxib group (-39.5 mm) was significantly greater than the placebo group (-33.3 mm) (p=0.001 for CS and p=0.009 for celecoxib), while no difference observed between CS and celecoxib. Similar trend for the LI, as reduction in this metric in the CS group (-4.7) and celecoxib group (-4.6) was significantly greater than the placebo group (-3.7) (p=0.023 for CS and p=0.015 for celecoxib), no difference was observed between CS and celecoxib. Both secondary endpoints (MCII and PASS) at day 182 improved significantly in the CS and celecoxib groups. All treatments demonstrated excellent safety profiles. CONCLUSION: A 800 mg/day pharmaceutical-grade CS is superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee osteoarthritis (OA) patients. This formulation of CS should be considered a first-line treatment in the medical management of knee OA.
- Klíčová slova
- chondroitin sulfate, function, knee osteoarthritis, pain, treatment,
- MeSH
- artróza kolenních kloubů farmakoterapie patofyziologie MeSH
- celekoxib terapeutické užití MeSH
- chondroitinsulfáty terapeutické užití MeSH
- dvojitá slepá metoda MeSH
- inhibitory cyklooxygenasy 2 terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- měření bolesti MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- celekoxib MeSH
- chondroitinsulfáty MeSH
- inhibitory cyklooxygenasy 2 MeSH
Geranyl flavones have been studied as compounds that potentially can be developed as anti-inflammatory agents. A series of natural geranylated flavanones was isolated from Paulownia tomentosa fruits, and these compounds were studied for their anti-inflammatory activity and possible mechanism of action. Two new compounds were characterized [paulownione C (17) and tomentodiplacone O (20)], and all of the isolated derivatives were assayed for their ability to inhibit cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX). The compounds tested showed variable degrees of activity, with several of them showing activity comparable to or greater than the standards used in COX-1, COX-2, and 5-LOX assays. However, only the compound tomentodiplacone O (20) showed more selectivity against COX-2 versus COX-1 when compared with ibuprofen. The ability of the test compounds to interact with the above-mentioned enzymes was supported by docking studies, which revealed the possible incorporation of selected test substances into the active sites of these enzymes. Furthermore, one of the COX/LOX dual inhibitors, diplacone (14) (a major geranylated flavanone of P. tomentosa), was studied in vitro to obtain a proteomic overview of its effect on inflammation in LPS-treated THP-1 macrophages, supporting its previously observed anti-inflammatory activity and revealing the mechanism of its anti-inflammatory effect.
- MeSH
- antiflogistika chemie izolace a purifikace farmakologie MeSH
- arachidonát-5-lipoxygenasa metabolismus MeSH
- cyklooxygenasa 1 metabolismus MeSH
- cyklooxygenasa 2 metabolismus MeSH
- flavonoidy chemie izolace a purifikace farmakologie MeSH
- inhibitory cyklooxygenasy 2 chemie izolace a purifikace farmakologie MeSH
- inhibitory lipoxygenas chemie izolace a purifikace farmakologie MeSH
- Magnoliopsida chemie MeSH
- molekulární struktura MeSH
- ovoce chemie MeSH
- proteomika * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antiflogistika MeSH
- arachidonát-5-lipoxygenasa MeSH
- cyklooxygenasa 1 MeSH
- cyklooxygenasa 2 MeSH
- flavonoidy MeSH
- inhibitory cyklooxygenasy 2 MeSH
- inhibitory lipoxygenas MeSH
OBJECTIVES: Celecoxib is a nonsteroidal anti-inflammatory drug inhibiting enzyme cyclooxygenase-2 (COX-2). The drug was introduced in 1990s. In the work presented here, affinity of celecoxib to enzyme acetylcholinesterase (AChE) is inferred. METHODS: Inhibition of human AChE by celecoxib was tested using standard spectrophotometric Ellman´s method and extrapolation of experimental data by Dixon plot. Interaction between AChE and celecoxib was also predicted by molecular docking using Swiss dock software. RESULTS: A non-competitive mechanism of inhibition was revealed and equilibrium inhibitory constant equal to 313±40 µmol/l was determined. Comparing to AChE, celecoxib was not proved as an inhibitor of enzyme butyrylcholinesterase (BChE). The lowest ΔG was equal to -7.78 kcal/mol. In this case, celecoxib stacked sulfonamide moiety between TYR 337 and TYR 341 of alfa anionic subsite of active site. Cation-Π interactions appears to be responsible for the inhibition. CONCLUSIONS: Though the here revealed and characterized inhibition has lower effect in real conditions than inhibition of COX-2, the inhibitory effect would be utilized in the next research and development of new AChE inhibitors.
- MeSH
- acetylcholinesterasa účinky léků MeSH
- celekoxib farmakologie MeSH
- cholinesterasové inhibitory farmakologie MeSH
- inhibitory cyklooxygenasy 2 farmakologie MeSH
- kyselina dithionitrobenzoová MeSH
- lidé MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- celekoxib MeSH
- cholinesterasové inhibitory MeSH
- inhibitory cyklooxygenasy 2 MeSH
- kyselina dithionitrobenzoová MeSH
In this open-label, laboratory-blinded, 2-way single dose study in 24 volunteers of both sexes we found that (1) nabumetone reaches mean Cmax ± SD of 0.56 ± 0.20 mg·L at mean tmax of 8.63 ± 7.05 hours, and mean area under the curve (AUC)last of 18.07 ± 7.19 h·mg·L; (2) there are no statistically significant differences between both sexes in pharmacokinetics of nabumetone; (3) 6-methoxy-2-naphthylacetic acid (6-MNA) reaches higher AUClast in men compared with women (mean ± SD, 721.23 ± 185.53 h·mg·L and 545.27 ± 97.69 h·mg·L, respectively; P = 0.013); (4) there is lower 6-MNA clearance in men (0.65 ± 0.22 L·h) in comparison with women (0.88 ± 0.18 L·h, P = 0.019), (5) intersubject variability of nabumetone and 6-MNA is between 35%-45% and 10%-30% for all assessed pharmacokinetics parameters (AUClast, Cmax, partial AUC values); (6) intrasubject variability (ISCV) for AUClast is low, 15.59% and 6.40% for nabumetone and 6-MNA, respectively, (7) ISCV for Cmax is 13.66% and 5.42% for nabumetone and 6-MNA, respectively. Nabumetone thus belongs to compounds with low to moderate ISCV and therefore this product is expected to produce consistent effects in clinical practice.
- MeSH
- butanony aplikace a dávkování farmakokinetika MeSH
- dospělí MeSH
- inhibitory cyklooxygenasy 2 aplikace a dávkování farmakokinetika MeSH
- kyseliny naftalenoctové farmakokinetika MeSH
- lidé MeSH
- mladý dospělý MeSH
- nabumeton MeSH
- plocha pod křivkou MeSH
- sexuální faktory MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- Názvy látek
- 6-methoxy-2-naphthylacetic acid MeSH Prohlížeč
- butanony MeSH
- inhibitory cyklooxygenasy 2 MeSH
- kyseliny naftalenoctové MeSH
- nabumeton MeSH
