2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling

Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positron-emitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation.

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Synthesis of18F-labelled cyclooxygenase-2 (COX-2) inhibitors via Stille reaction with 4-[18F]fluoroiodobenzene as radiotracers for positron emission tomography (PET)

Organic & Biomolecular Chemistry ◽

10.1039/b412871k ◽

2005 ◽

Vol 3 (3) ◽

pp. 503-507 ◽

Cited By ~ 47

Author(s):

Frank R. Wüst ◽

Aileen Höhne ◽

Peter Metz

Keyword(s):

Positron Emission Tomography ◽

Cyclooxygenase 2 ◽

Emission Tomography ◽

Stille Reaction ◽

Positron Emission ◽

Cox 2 ◽

Cox 2 Inhibitors

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Involvement of cyclooxygenase 2 (COX-2) in intrinsic tone of isolated guinea pig

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-215 ◽

1995 ◽

Vol 73 (11) ◽

pp. 1561-1567 ◽

Cited By ~ 21

Author(s):

L. Charette ◽

C. Misquitta ◽

J. Guay ◽

D. Riendeau ◽

T. R. Jones

Keyword(s):

Guinea Pig ◽

Time Course ◽

Cyclooxygenase 2 ◽

Maximal Response ◽

Pharmacological Agents ◽

Cyclooxygenase 1 ◽

Inflammatory Drugs ◽

Cox 2 ◽

Cox 2 Inhibitors ◽

Cox 1

Indomethacin and related nonsteroidal anti-inflammatory drugs relax prostanoid-dependent intrinsic tone of isolated guinea pig trachea by inhibiting cyclooxygenase (COX). Recently, a second isoform of COX (COX-2) was discovered, which differed from COX-1 with respect to protein structure, transcriptional regulation, and susceptibility to inhibition by pharmacological agents. It is now known that indomethacin nonselectively inhibits COX-1 and COX-2, whereas NS-398 is a selective inhibitor of COX-2. In the present study we compared the activity of a selective (NS-398) and nonselective (indomethacin) COX-2 inhibitor on intrinsic tone of isolated guinea pig trachea. NS-398 ≥ indomethacin produced a reversal of intrinsic tone with a similar concentration-dependent (10 nM to 1 μM) time course (Tmax approximately 20–45 min), potency (EC50 1.7 and 5.6 nM, respectively), and maximal response. Contractions to cholinergic nerve stimulation (45 V, 0.5 ms, 0.1–32 Hz) and histamine were similarly modulated in tissues relaxed with the selective or nonselective COX-2 inhibitors. Immunoblot analyses showed that COX-2 protein synthesis was induced in both the cartilage and smooth muscle portions of the trachea during changes in intrinsic tone. These findings are consistent with pharmacological results and provide the first demonstration that prostanoid tone in isolated guinea pig trachea is dependent on COX-2 activity. The results also suggest that the activity of indomethacin in this preparation is likely related to COX-2 inhibition.Key words: cyclooxygenase 2, relaxation, guinea pig trachea, cyclooxygenase 1.

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Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Molecules ◽

10.3390/molecules24152791 ◽

2019 ◽

Vol 24 (15) ◽

pp. 2791 ◽

Cited By ~ 3

Author(s):

Ritawidya ◽

Ludwig ◽

Briel ◽

Brust ◽

Scheunemann

Keyword(s):

Potent Inhibitor ◽

Liver Microsomes ◽

Emission Tomography ◽

Inhibitory Potency ◽

Positron Emission ◽

Neuropsychiatric Diseases ◽

Further Development ◽

The Brain

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.

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Studies in 3,4-diaryl-1,2,5-oxadiazoles and their N-oxides: Search for better COX-2 inhibitors

Acta Pharmaceutica ◽

10.2478/v10007-007-0002-z ◽

2007 ◽

Vol 57 (1) ◽

pp. 13-30 ◽

Cited By ~ 20

Author(s):

Mange Yadav ◽

Shrikant Shirude ◽

Devendra Puntambekar ◽

Pinkal Patel ◽

Hetal Prajapati ◽

...

Keyword(s):

Enzyme Inhibition ◽

Docking Studies ◽

Inflammatory Activity ◽

Rat Paw Edema ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors ◽

Cox 1

Studies in 3,4-diaryl-1,2,5-oxadiazoles and theirN-oxides: Search for better COX-2 inhibitorsA series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazoleN-oxides were prepared and evaluated for COX-2 and COX-1 binding affinityin vitroand for anti-inflammatory activity by the rat paw edema method.p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazoleN-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 μmol L-1and COX-1 enzyme inhibition of 44% at 88 μmol L-1concentrations, but showed very lowin vivoanti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 μmol L-1) and higher COX-1 enzyme inhibition (53% at 88 μmol L-1) but, markedin vivoanti-inflammatory activity (71% at 25 mg kg-1)vs.celecoxib (48% at 12.5 mg kg-1). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest thatp-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.

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Cyclooxygenase-2 inhibition reduces stress-induced affective pathology

eLife ◽

10.7554/elife.14137 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 25

Author(s):

Joyonna Carrie Gamble-George ◽

Rita Baldi ◽

Lindsay Halladay ◽

Adrina Kocharian ◽

Nolan Hartley ◽

...

Keyword(s):

Anxiety Disorders ◽

Basolateral Amygdala ◽

Cannabinoid Receptor ◽

Ex Vivo ◽

Receptor Activation ◽

Cyclooxygenase 2 ◽

Novel Treatment ◽

Cox 2 ◽

Cox 2 Inhibitors

Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice. We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation. Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.

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Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.6.r1496 ◽

2000 ◽

Vol 278 (6) ◽

pp. R1496-R1505 ◽

Cited By ~ 57

Author(s):

Yasushi Takahashi ◽

Christine Roman ◽

Sylvain Chemtob ◽

Mary M. Tse ◽

Emil Lin ◽

...

Keyword(s):

Ductus Arteriosus ◽

Plasma Concentrations ◽

Additional Increase ◽

Cox Inhibitors ◽

Fetal Plasma ◽

Cox 2 ◽

Cox 2 Inhibitors ◽

Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE2 and 6ketoPGF1α production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 ± 0.6 μg/ml, mean ± standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE2 and 6ketoPGF1α. Indomethacin (0.7 ± 0.2 μg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.

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Design, Synthesis, and Evaluation of an18F-Labeled Radiotracer Based on Celecoxib-NBD for Positron Emission Tomography (PET) Imaging of Cyclooxygenase-2 (COX-2)

ChemMedChem ◽

10.1002/cmdc.201500287 ◽

2015 ◽

Vol 10 (10) ◽

pp. 1635-1640 ◽

Cited By ~ 21

Author(s):

Jatinder Kaur ◽

Ole Tietz ◽

Atul Bhardwaj ◽

Alison Marshall ◽

Jenilee Way ◽

...

Keyword(s):

Positron Emission Tomography ◽

Pet Imaging ◽

Cyclooxygenase 2 ◽

Emission Tomography ◽

Design Synthesis ◽

Positron Emission ◽

Cox 2

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In Silico Molecular Docking Studies of Lichen Metabolites against Cyclooxygenase-2 Enzyme

Bangladesh Pharmaceutical Journal ◽

10.3329/bpj.v18i2.24304 ◽

2015 ◽

Vol 18 (2) ◽

pp. 90-96 ◽

Cited By ~ 4

Author(s):

Mohammad Firoz Khan ◽

Sabreena Aleem Nabila ◽

Ridwan Bin Rashid ◽

Mohammad Sharifur Rahman ◽

Abu Asad Chowdhury ◽

...

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

Usnic Acid ◽

Cyclooxygenase 2 ◽

Therapeutic Effects ◽

Lichen Metabolites ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors

Cyclooxygenase-2 (COX-2) is an inducible enzyme that causes inflammation. COX-2 inhibitors are clinically effective anti-inflammatory agents with less gastrointestinal and renal toxicities. However, they lack anti-thrombotic activity and hence lead to increased incidences of adverse cardiovascular thrombotic events, including myocardial infarction. Therefore, there is still need to develop COX-2 inhibitors with better therapeutic effects and tolerability. The aim of the present study is to explore the anti-inflammatory activity of five lichen metabolites by conducting virtual screenings. In this regard, molecular docking simulations were carried out for the lichen metabolites namely atranorin, diffractic acid, lecanoric acid, salazinic acid and usnic acid with human COX-2 enzyme and the docked results were compared with the standard reference ligands (Celecoxib and Rofecoxib). Among all the docked ligands, the lecanoric acid demonstrated best binding affinity -9.83 kcal/mol followed by atranorin (-8.7 kcal/mol) and diffractic acid (-8.6 kcal/mol) which are comparable to the reference ligands celecoxib (-12.3 kcal/mol) and rofecoxib (-11.2 kcal/mol). The salazinic acid and usnic acid has shown binding affinity of -7.9 kcal/mol and -4.7 kcal/mol, respectively. Moreover, all the ligands except atranorin and diffractic acid satisfied Lipinskis rule of 5. From the docking results it was revealed that the lichen metabolites might have inhibitory activity against COX-2 enzyme, and are expected to be useful in conducting in vivo anti-inflammatory screenings on animal model which may lead to the development of more effective and potent new chemical entities with anti-inflammatory properties.Bangladesh Pharmaceutical Journal 18(2): 90-96, 2015

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Abnormal megakaryopoiesis and platelet function in cyclooxygenase-2-deficient mice

Thrombosis and Haemostasis ◽

10.1160/th14-10-0872 ◽

2015 ◽

Vol 114 (12) ◽

pp. 1218-1229 ◽

Cited By ~ 6

Author(s):

Patrizia Amadio ◽

Bianca Rocca ◽

Maurizio Pesce ◽

Kellie R. Machlus ◽

Franco O. Ranelletti ◽

...

Keyword(s):

Platelet Function ◽

Cyclooxygenase 2 ◽

Epinephrine Injection ◽

Fibrinogen Binding ◽

Cox 2 ◽

Lineage Markers ◽

Cox 1 ◽

Platelet Formation

SummaryPrevious studies suggest that cyclooxygenase-2 (COX-2) might influence megakaryocyte (MK) maturation and platelet production in vitro. Using a gene deletion model, we analysed the effect of COX-2 deficiency on megakaryopoiesis and platelet function. COX-2-/- mice (10–12 weeks old) have hyper-responsive platelets as suggested by their enhanced aggregation, TXA2 biosynthesis, CD62P and CD41/CD61 expression, platelet-fibrinogen binding, and increased thromboembolic death after collagen/epinephrine injection compared to wild-type (WT). Moreover, increased platelet COX-1 expression and reticulated platelet fraction were observed in COX-2-/- mice while platelet count was similar to WT. MKs were significantly reduced in COX-2-/- bone marrows (BMs), with high nuclear/cytoplasmic ratios, low ploidy and poor expression of lineage markers of maturation (CD42d, CD49b). However, MKs were significantly increased in COX-2-/- spleens, with features of MK maturation markers which were not observed in MKs of WT spleens. Interestingly, the expression of COX-1, prostacyclin and PGE2 synthases and prostanoid pattern were modified in BMs and spleens of COX-2-/- mice. Moreover, COX-2 ablation reduced the percentage of CD49b+ cells, the platelet formation and the haematopoietic stem cells in bone marrow and increased their accumulation in the spleen. Splenectomy decreased peripheral platelet number, reverted their hyper-responsive phenotype and protected COX-2-/- mice from thromboembolism. Interestingly, fibrosis was observed in spleens of old COX-2-/- mice (28 weeks old). In conclusion, COX-2 deletion delays BM megakaryopoiesis promoting a compensatory splenic MK hyperplasia, with a release of hyper-responsive platelets and increased thrombogenicity in vivo. COX-2 seems to contribute to physiological MK maturation and pro-platelet formation.

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