scholarly journals Synthesis and theoretical activity evaluation of a new steroid-oxazolone derivative against COX1-1 and COX-2

2019 ◽  
Vol 9 (4) ◽  
pp. 4107-4113
Keyword(s):  
Elemental Analysis ◽  
Cox Inhibitors ◽  
Activity Evaluation ◽  
Docking Model ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Cox 1

There are some reports for the preparation of several drugs as cyclooxygenase (COX) inhibitors; however, some reagents used in the preparation are expensive and difficult to handle. The aim of this study was to synthesize a steroid-oxazolone derivativeusing some reactions such as i) hydroxylation-amiination; ii) amidation; iii) alkynyl-addition; iv) aldolization and iv) imination. In addition, a theoretical ass was carried out to evaluate the interaction of both COX-1 and COX-2 with the steroid-oxazolone derivativeusing indomethacin and rofecoxib as controls in a docking model. The structure of the compounds obtained was confirmed through elemental analysis, spectroscopy and spectrometry data. The results showed that there are differences between the interaction of the steroidoxazolone derivativewith both COX 1 and COX 2 compared with the bound of indomethacin and rofecoxib with this type of enzymes. These data suggest that the steroid-oxazolone derivativecould be a good candidate as COX-inhibitor translated as a possible drug for treatment of pain.

Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

2008 ◽  
Vol 294 (1) ◽  
pp. H145-H155 ◽  
Author(s):  
Ting-Ting Hong ◽  
Jinbao Huang ◽  
Terrance D. Barrett ◽  
Benedict R. Lucchesi
Keyword(s):  
Coronary Artery ◽  
Vascular Reactivity ◽  
Thrombus Formation ◽  
Normal Coronary Artery ◽  
Cox Inhibitors ◽  
Inflammatory Conditions ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

This study was designed to determine the effect of inhibitors of cyclooxygenase (COX)-1, COX-2, and the nonselective COX inhibitor naproxen on coronary vasoactivity and thrombogenicity under baseline and lipopolysaccharide (LPS)-induced inflammatory conditions. We hypothesize that endothelial COX-1 is the primary COX isoform in the canine normal coronary artery, which mediates arachidonic acid (AA)-induced vasodilatation. However, COX-2 can be induced and overexpressed by inflammatory mediators and becomes the major local COX isoform responsible for the production of antithrombotic prostaglandins during systemic inflammation. The interventions included the selective COX-1 inhibitor SC-560 (0.3 mg/kg iv), the selective COX-2 inhibitor nimesulide (5 mg/kg iv), or the nonselective COX inhibitor naproxen (3 mg/kg iv). The selective prostacyclin (IP) receptor antagonist RO-3244794 (RO) was used as an investigational tool to delineate the role of prostacyclin (PGI2) in modulating vascular reactivity. AA-induced vasodilatation of the left circumflex coronary artery was suppressed to a similar extent by each of the COX inhibitors and RO. The data suggest that AA-induced vasodilatation in the normal coronary artery is mediated by a single COX isoform, the constitutive endothelial COX-1, which is reported to be susceptible to COX-2 inhibitors. The effect of the COX inhibitors on thrombus formation was evaluated in a model of carotid artery thrombosis secondary to electrolytic-induced vessel wall injury. Pretreatment with LPS (0.5 mg/kg iv) induced a systemic inflammatory response and prolonged the time-to-occlusive thrombus formation, which was reduced in the LPS-treated animals by the administration of nimesulide. In contrast, neither SC-560 nor naproxen influenced the time to thrombosis in the animals pretreated with LPS. The data are of significance in view of reported adverse cardiovascular events observed in clinical trials involving the use of selective COX-2 inhibitors, thereby suggesting that the endothelial constitutive COX-1 and the inducible vascular COX-2 serve important functions in maintaining vascular homeostasis.

scholarly journals DESIGN, SYNTHESIS AND BIOLOGICAL SCREENING OF AMINOACETYLENIC TETRAHYDROPHTHALIMIDE ANALOGUES AS NOVEL CYCLOOXYGENASE (COX) INHIBITORS

2017 ◽  
Vol 9 (2) ◽  
pp. 160
Author(s):  
Ahmed Basim ◽  
Zuhair A. Muhi Eldeen ◽  
Elham N. Al-kaissi ◽  
Ghadeer Suaifan ◽  
Mohammad A. Ghattas ◽  
...  
Keyword(s):  
Elemental Analysis ◽  
Inhibitory Activity ◽  
Aryl Group ◽  
Design Synthesis ◽  
Cox Inhibitors ◽  
H Nmr ◽  
Phthalimide Derivative ◽  
Cox 2 ◽  
Cox 1 ◽  
C Nmr

<p><strong>Objective: </strong>To design and synthesise a new amino acetylenic tetrahydro phthalimide derivative and investigate their selective inhibitory activity to COXs.</p><p><strong>Methods: </strong>Aminoacetylenic tetrahydro phthalimide derivatives were synthesised by alkylation of tetrahydro phthalimide with propargyl bromide afforded 2-(prop-2-yn-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione. The alkylated tetrahydro phthalimide was subjected to Mannich reaction afforded the desired amino acetylenic tetra phthalimide derivatives (AZ 1-6). The elemental analysis was indicated by the EuroEA elemental analyzer and biological characterization was via IR, <sup>1</sup>H-NMR, [13]C-NMR, DSC was determined with the aid of Bruker FT-IR and Varian 300 MHz spectrometer and DMSO-d<sub>6</sub> as a solvent, molecular docking was done using the Autodock Tool software (version 4.2). ChemBioDraw was used in the drawing of our schemes.</p><p><strong>Results</strong>:<strong> </strong>The IR, <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, DSC and elemental analysis were consistent with the assigned structures. The designers of the compounds as COXs inhibitor activity were based on the nationalisation of the important criteria that provide effective inhibitory binding with COXs–receptor. The results indicated that the synthesised compounds (AZ1-6) showed a close similarity in the binding affinity to both COXs and may be more specific to COX-1. AZ-5 showed the highest % of inhibition for COX-1 even better than aspirin. Which may suggest that the aryl group is required for COX-2 inhibition.</p><p><strong>Conclusion: </strong>For the first time, we indicate the requirement of aromaticity in COX-2 structural inhibitory activity. </p>

Mechanisms underlying the contraction induced by bradykinin in the guinea pig epithelium-denuded trachea

2002 ◽  
Vol 80 (4) ◽  
pp. 360-367 ◽  
Author(s):  
Valfredo Schlemper ◽  
João B Calixto
Keyword(s):  
Nitric Oxide ◽  
Guinea Pig ◽  
Rank Order ◽  
Nitric Oxide Synthase Inhibitor ◽  
Cox Inhibitors ◽  
Cyclooxygenase 1 ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Synthase Inhibitor ◽  
Cox 1

This study investigates some of the mechanisms by which bradykinin (BK) triggers contraction of epithelium-denuded strips of guinea pig trachea (GPT). Cumulative or single additions of BK, T-BK, L-BK, or ML-BK in the presence of captopril (30 µM) produced graded GPT contractions with the following rank order of potency (EC50 level): T-BK (31.3 nM) > BK (40.0 nM) > L-BK (56.0 nM) > ML-BK (77.0 nM). BK-induced contraction (100 nM) in GPT was completely inhibited by either HOE 140 or NPC 17731 with mean IC50 values of 17 and 217 nM, respectively. Addition of BK (100 nM) at 30 min intervals, induced progressive tachyphylaxis, which was complete after 4 h. The tachyphylaxis induced by BK was unaffected by L-NOARG (nitric oxide synthase inhibitor, 100 µM) or valeryl salicylate (a cyclooxygenase-1 (COX-1) inhibitor, 30 µM), but was prevented by a low concentration of indomethacin, diclofenac (non-selective COX inhibitors, 3 nM each) or by NS 398 (a COX-2 inhibitor, 10 nM). Furthermore, higher concentrations of indomethacin, diclofenac, phenidone (a lypooxygenase (LOX) and COX inhibitor), or NS 398, caused graded inhibition of BK-induced contraction, with mean IC50 values of 0.28, 0.08, 46.37, and 0.15 µM, respectively. Together, these results suggest that BK-induced contraction in GPT involves activation of B2 receptors and release of prostanoids from COX-2 pathway. Furthermore, the tachyphylaxis induced by BK was insensitive to the nitric oxide and COX-1 inhibitors, but was prevented by non-selective and selective COX-2 inhibitors, indicating a mediation via COX-2-derived arachidonic acid metabolites.Key words: guinea pig trachea, bradykinin, B2 receptors, desensitization, prostaglandins.

Prostaglandins mediate tonic contraction of the guinea pig and human gallbladder

2007 ◽  
Vol 292 (1) ◽  
pp. G409-G418 ◽  
Author(s):  
Ping Cong ◽  
Zuo-Liang Xiao ◽  
Piero Biancani ◽  
Jose Behar
Keyword(s):  
Protein Expression ◽  
Tonic Contraction ◽  
Human Gallbladder ◽  
Small Interference Rna ◽  
Cox Inhibitors ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Dose Dependent Decrease ◽  
Dose Dependent ◽  
Cox 1

The gallbladder (GB) maintains tonic contraction modulated by neurohormonal inputs but generated by myogenic mechanisms. The aim of these studies was to examine the role of prostaglandins in the genesis of GB myogenic tension. Muscle strips and cells were treated with prostaglandin agonists, antagonists, cyclooxygenase (COX) inhibitors, and small interference RNA (siRNA). The results show that PGE2, thromboxane A2 (TxA2), and PGF2α cause a dose-dependent contraction of muscle strips and cells. However, only TxA2 and PGE2 (E prostanoid 1 receptor type) antagonists induced a dose-dependent decrease in tonic tension. A COX-1 inhibitor decreased partially the tonic contraction and TxB2 (TxA2 stable metabolite) levels; a COX-2 inhibitor lowered the tonic contraction partially and reduced PGE2 levels. Both inhibitors and the nonselective COX inhibitor indomethacin abolished the tonic contraction. Transfection of human GB muscle strips with COX-1 siRNA partially lowered the tonic contraction and reduced COX-1 protein expression and TxB2 levels; COX-2 siRNA also partially reduced the tonic contraction, the protein expression of COX-2, and PGE2. Stretching muscle strips by 1, 2, 3, and 4 g increased the active tension, TxB2, and PGE2 levels; a COX-1 inhibitor prevented the increase in tension and TxB2; and a COX-2 inhibitor inhibited the expected rise in tonic contraction and PGE2. Indomethacin blocked the rise in tension and TxB2 and PGE2 levels. We conclude that PGE2 generated by COX-2 and TxA2 generated by COX-1 contributes to the maintenance of GB tonic contraction and that variations in tonic contraction are associated with concomitant changes in PGE2 and TxA2 levels.

Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus

1999 ◽  
Vol 276 (3) ◽  
pp. R913-R921 ◽  
Author(s):  
Ronald I. Clyman ◽  
Pierre Hardy ◽  
Nahid Waleh ◽  
Yao Qi Chen ◽  
Françoise Mauray ◽  
...  
Keyword(s):  
Significant Role ◽  
Ductus Arteriosus ◽  
Late Gestation ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Fetal Lamb ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.

Key role for constitutive cyclooxygenase-2 of MDCK cells in basal signaling and response to released ATP

2001 ◽  
Vol 281 (2) ◽  
pp. C524-C531 ◽  
Author(s):  
Rennolds S. Ostrom ◽  
Caroline Gregorian ◽  
Ryan M. Drenan ◽  
Kathryn Gabot ◽  
Brinda K. Rana ◽  
...  
Keyword(s):  
Cell Function ◽  
Mdck Cells ◽  
Second Messengers ◽  
Atp Release ◽  
Cox Inhibitors ◽  
Cox 2 ◽  
Factor Α ◽  
Biochemical Activation ◽  
Camp Formation ◽  
Cox 1

Madin-Darby canine kidney (MDCK) cells release ATP upon mechanical or biochemical activation, initiating P2Y receptor signaling that regulates basal levels of multiple second messengers, including cAMP ( J Biol Chem 275: 11735–11739, 2000). Data shown here document inhibition of cAMP formation by Gd3+ and niflumic acid, channel inhibitors that block ATP release. cAMP production is stimulated via Ca2+-dependent activation of cytosolic phospholipase A2, release of arachidonic acid (AA), and cyclooxygenase (COX)-dependent production of prostaglandins, which activate prostanoid receptors coupled to Gs and adenylyl cyclase. In the current investigation, we assessed the expression and functional role of the two known isoforms of COX, COX-1 and COX-2. Treatment of cells with either a COX-1-selective inhibitor, SC-560, or COX-2-selective inhibitors, SC-58125 or NS-398, inhibited basal and UTP-stimulated cAMP levels. COX inhibitors also decreased forskolin-stimulated cAMP formation, implying this response is in part attributable to an action of AA metabolites. These findings imply an important role for the inducible form of COX, COX-2, under basal conditions. Indeed, COX-2 expression was readily detectable by immunoblot, and treatments that induce or reduce COX-2 expression in other cells (interleukin-1β, tumor necrosis factor-α, phorbol ester, or dexamethasone) had minimal or no effect on the levels of COX-2 immunoreactivity. RT-PCR using isoform-specific primers detected COX-2 mRNA. We conclude that COX-2 is constitutively expressed in MDCK-D1 cells and participates in basal and P2Y2-mediated signaling, implying a key role for COX-2 in regulation of epithelial cell function.

scholarly journals Cyclooxygenases Inhibitors Efficiently Induce Cardiomyogenesis in Human Pluripotent Stem Cells

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 554 ◽  
Author(s):  
Harshal Nemade ◽  
Aviseka Acharya ◽  
Umesh Chaudhari ◽  
Erastus Nembo ◽  
Filomain Nguemo ◽  
...  
Keyword(s):  
Wnt Signaling Pathway ◽  
Calcium Transient ◽  
Cardiac Differentiation ◽  
Cyclooxygenase Inhibitors ◽  
Cox Inhibitors ◽  
Screening Model ◽  
Cox 2 ◽  
Transient Measurements ◽  
Cox 1

Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless (Wnt) signaling pathway has emerged as the key regulator of cardiomyogenesis. In this study, we evaluated the effects of cyclooxygenase inhibitors on cardiac differentiation of hPSCs. Cardiac differentiation was performed by adherent monolayer based method using 4 hPSC lines (HES3, H9, IMR90, and ES4SKIN). The efficiency of cardiac differentiation was evaluated by flow cytometry and RT-qPCR. Generated hPSC-CMs were characterised using immunocytochemistry, electrophysiology, electron microscopy, and calcium transient measurements. Our data show that the COX inhibitors Sulindac and Diclofenac in combination with CHIR99021 (GSK-3 inhibitor) efficiently induce cardiac differentiation of hPSCs. In addition, inhibition of COX using siRNAs targeted towards COX-1 and/or COX-2 showed that inhibition of COX-2 alone or COX-1 and COX-2 in combination induce cardiomyogenesis in hPSCs within 12 days. Using IMR90-Wnt reporter line, we showed that inhibition of COX-2 led to downregulation of Wnt signalling activity in hPSCs. In conclusion, this study demonstrates that COX inhibition efficiently induced cardiogenesis via modulation of COX and Wnt pathway and the generated cardiomyocytes express cardiac-specific structural markers as well as exhibit typical calcium transients and action potentials. These cardiomyocytes also responded to cardiotoxicants and can be relevant as an in vitro cardiotoxicity screening model.

scholarly journals Comparative Analysis of Pharmacologic and/or Genetic Disruption of Cyclooxygenase-1 and Cyclooxygenase-2 Function in Female Reproduction in Mice*

Endocrinology ◽  
2001 ◽  
Vol 142 (7) ◽  
pp. 3198-3206 ◽  
Author(s):  
Jeff Reese ◽  
Xuemei Zhao ◽  
Wen-Ge Ma ◽  
Naoko Brown ◽  
Timothy J. Maziasz ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Synergistic Effects ◽  
Female Reproduction ◽  
Cox Inhibitors ◽  
Cyclooxygenase 1 ◽  
Simultaneous Inhibition ◽  
Cox 2 ◽  
Alternative Sources ◽  
First Time ◽  
Cox 1

Abstract Cyclooxygenase (COX)-derived prostaglandins are critical in female reproduction. Gene targeting studies show that ovulation, fertilization, implantation, and decidualization are defective in COX-2 deficient mice. We used genetic and pharmacologic approaches to perturb COX function and examine the differential and synergistic effects of inhibition of COX-1, COX-2, or of both isoforms on reproductive outcomes during early pregnancy in mice. The results demonstrate that simultaneous inhibition of COX-1 and COX-2 produces more severe effects on early pregnancy events than inhibition of either isoform alone. The effects of pharmacological inhibition of COX-2 on female reproductive functions were less severe than the null mutation of the COX-2 gene. A combined approach showed that COX-2 inhibition in COX-1−/− mice induced complete reproductive failure, suggesting a lack of alternative sources of prostaglandin synthesis. This investigation raises caution regarding the indiscriminate use of COX inhibitors and shows for the first time the distinct and overlapping pathways of the cyclooxygenase systems in female reproduction.

Synthesis and evaluation of new benzimidazole-based COX inhibitors: a naproxen-like interaction detected by STD-NMR

RSC Advances ◽  
2015 ◽  
Vol 5 (61) ◽  
pp. 49098-49109 ◽  
Author(s):  
Luísa C. R. Carvalho ◽  
Daniela Ribeiro ◽  
Raquel S. G. R. Seixas ◽  
Artur M. S. Silva ◽  
Mariana Nave ◽  
...  
Keyword(s):  
Pharmacological Activity ◽  
Cox Inhibitors ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Std Nmr ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Non-steroidal anti-inflammatory drugs exert their pharmacological activity through inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2).

Key role for cyclooxygenase-2 in PGE2 and PGF2α receptor regulation and cerebral blood f low of the newborn

1997 ◽  
Vol 273 (4) ◽  
pp. R1283-R1290 ◽  
Author(s):  
Ding-You Li ◽  
Pierre Hardy ◽  
Daniel Abran ◽  
Ana-Katherine Martinez-Bermudez ◽  
Anne-Marie Guerguerian ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Receptor Agonist ◽  
Prostaglandin E ◽  
Receptor Density ◽  
Cerebral Vasculature ◽  
Newborn Brain ◽  
Cox Inhibitor ◽  
Newborn Pigs ◽  
Cox 2 ◽  
Cox 1

Ibuprofen, a cyclooxygenase (COX) inhibitor nonselective for either COX-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E2(PGE2) and PGF2α receptors in newborn pigs. COX-2 was shown to be the predominant form of COX and the main catalyst of prostaglandin synthesis in the newborn brain. We proceeded to establish direct evidence that COX-2-generated prostaglandins govern PGE2 and PGF2α receptor density and function in the cerebral vasculature of the newborn. Hence, we determined PGE2 and PGF2α receptor density and functions in brain vasculature by using newborn pigs treated with saline, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibitors (DUP-697 and NS-398). Newborn brain PGE2 and PGF2α concentrations were significantly reduced by ibuprofen, DUP-697, and NS-398 but not by valerylsalicylate. In newborn pigs treated with DUP-697, NS-398, and ibuprofen, PGE2 and PGF2α receptor densities in brain microvessels were increased to adult levels; there was also a significant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE2(EP1 receptor agonist), M&B-28767 (EP3 receptor agonist), PGF2α, and fenprostalene (PGF2αanalog). Treatment with ibuprofen or DUP-697 also increased the upper blood pressure limit of cerebral cortex and periventricular blood flow autoregulation from 85 to ≥125 mmHg (uppermost blood pressure studied). However, valerylsalicylate treatment did not affect cerebrovascular PGE2 and PGF2α receptors, IP3 production, or vasoconstrictor effects in newborn animals. These in vivo and in vitro observations indicate that COX-2 is mainly responsible for the regulation of PGE2 and PGF2α receptors and their functions in the newborn cerebral vasculature.

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