Identification and optimisation of a novel series of pyrimidine based cyclooxygenase-2 (COX-2) inhibitors. Utilisation of a biotransformation approach

Beswick, Paul J.; Blackaby, Andrew P.; Bountra, C.; Brown, Terry; Browning, Kerry; Campbell, Ian B.; Corfield, John; Gleave, Robert J.; Guntrip, Steve B.; Hall, Richard M.; Hindley, Seán; Lambeth, P. F.; Lucas, Fiona; Mathews, Neil; Naylor, Alan; Player, Hazel; Price, Helen S.; Sidebottom, Phillip J.; Taylor, Nicolas L.; Webb, G. A.; Wiseman, Joanne O.

doi:10.1016/j.bmcl.2009.02.089

Cited by 19 publications

(5 citation statements)

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“…A representative agent 18 (Figure 4) exhibited a good combination of oral anti-inflammatory activity and in vitro COX-2 selectivity (COX-2 IC 50 = 0.12 µM; COX-1 IC 50 = 0.91 µM). In 2009, GlaxoSmithKline (GSK) scientists reported the development of a novel series of trifluoromethylpyrimidine based ring scaffolds ( 19 , COX-2 IC 50 = 206 nM; COX-1 IC 50 = 62000 nM) as highly potent and selective COX-2 inhibitors [43,44]. Accordingly, several diverse classes of selective COX-2 inhibitors have been reported and a thorough discussion is beyond the scope of this review [45].…”

Section: Selective Cox-2 Inhibitorsmentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

2010

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Ever since the discovery of aspirin, small molecule therapeutics have been widely prescribed to treat inflammation and pain. Aspirin and several small molecule NSAIDs are known to inhibit the enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2). Despite the success of NSAIDs to treat inflammatory disorders, the development of a clinically useful small molecule NSAIDs with decreased side effect profiles is an ongoing effort. The recent discovery and development of selective COX-2 inhibitors was a step toward this direction. Emerging trends are represented by the progress in the development of hybrid agents such as nitric oxide donor-NSAIDs (NO-NSAIDs) and dual COX/lipoxygenase (LOX) inhibitors. This review focuses on the recent advances in the rational design of small molecule NSAIDs in therapy.

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Section: Selective Cox-2 Inhibitorsmentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

2010

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“…A recent attempt from our research team transforming a successful in vitro fluorescence-labeled celecoxib derivative into a 18 F-labeled radiotracer also failed because no sufficient trapping in COX-2 expressing tumors was detected [ 22 ]. Based on that, the goal of the present study was to evaluate an alternative COX-2 radiotracer based on a pyrimidine scaffold [ 23 ] for the first time in vivo. We wanted to analyze if [ 18 F]Pyricoxib, which radiosynthesis we had developed recently, would be a better PET imaging probe for assessment of functional expression of COX-2 in a pre-clinical human colorectal cancer model in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

PET imaging of cyclooxygenase-2 (COX-2) in a pre-clinical colorectal cancer model

et al. 2016

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BackgroundCyclooxygenase-2 (COX-2) is the inducible isoform of the cyclooxygenase enzyme family. COX-2 is involved in tumor development and progression, and frequent overexpression of COX-2 in a variety of human cancers has made COX-2 an important drug target for cancer treatment. Non-invasive imaging of COX-2 expression in cancer would be useful for assessing COX-2-mediated effects on chemoprevention and radiosensitization using COX-2 inhibitors as an emerging class of anti-cancer drugs, especially for colorectal cancer. Herein, we describe the radiopharmacological analysis of [18F]Pyricoxib, a novel radiolabeled COX-2 inhibitor, for specific PET imaging of COX-2 in colorectal cancer.MethodsUptake of [18F]Pyricoxib was assessed in human colorectal cancer cell lines HCA-7 (COX-2 positive) and HCT-116 (COX-2 negative). Standard COX-2 inhibitors were used to test for specificity of [18F]Pyricoxib for COX-2 binding in vitro and in vivo. PET imaging, biodistribution, and radiometabolite analyses were included into radiopharmacological evaluation of [18F]Pyricoxib.ResultsRadiotracer uptake in COX-2 positive HCA-7 cells was significantly higher than in COX-2 negative HCT-116 cells (P < 0.05). COX-2 inhibitors, celecoxib, rofecoxib, and SC58125, blocked uptake of [18F]Pyricoxib in HCA-7 cells in a concentration-dependent manner. The radiotracer was slowly metabolized in mice, with approximately 60 % of intact compound after 2 h post-injection. Selective COX-2-mediated tumor uptake of [18F]Pyricoxib in HCA-7 xenografts was confirmed in vivo. Celecoxib (100 mg/kg) selectively blocked tumor uptake by 16 % (PET image analysis; P < 0.05) and by 51 % (biodistribution studies; P < 0.01).ConclusionsThe novel PET radiotracer [18F]Pyricoxib displays a promising radiopharmacological profile to study COX-2 expression in cancer in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0192-9) contains supplementary material, which is available to authorized users.

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“…A series of pyrimidine-based COX-2 inhibitors reported a ninefold boost in potency when the phenyl ring was exchanged for a cyclohexyl ring ( Fig. 3 F ) ( 58 ). Mn(CF 3 -PDP) 1 catalysis was applied to both isomeric aromatic series ( 57 and S43 ) and afforded a mixture of γ- and δ-ketones on the cyclohexyl rings in synthetically useful yields ( 58 , 49% γ:δ = 1:1.1, and S53/S54 56% γ:δ = 1:1.3, see SI Appendix ).…”

Section: Resultsmentioning

confidence: 99%

A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C–H oxidation of carbocyclic N -heterocycles

Chambers,

Weaver,

Kim

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles ( N -heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes are capable of direct site- and chemo-selective oxidation of a broad range of substrates but are not preparative. A chemoinformatic analysis underscored limited structural diversity of N -heterocyclic substrates oxidized using chemical methods relative to pharmaceutical chemical space. Here, we describe a preparative chemical method for direct aliphatic oxidation that tolerates a wide range of nitrogen functionality (chemoselective) and matches the site of oxidation (site-selective) of liver CYP450 enzymes. Commercial small-molecule catalyst Mn(CF 3 -PDP) selectively effects direct methylene oxidation in compounds bearing 25 distinct heterocycles including 14 out of 27 of the most frequent N -heterocycles found in U.S. Food and Drug Administration (FDA)-approved drugs. Mn(CF 3 -PDP) oxidations of carbocyclic bioisostere drug candidates (for example, HCV NS5B and COX-2 inhibitors including valdecoxib and celecoxib derivatives) and precursors of antipsychotic drugs blonanserin, buspirone, and tiospirone and the fungicide penconazole are demonstrated to match the major site of aliphatic metabolism obtained with liver microsomes. Oxidations are demonstrated at low Mn(CF 3 -PDP) loadings (2.5 to 5 mol%) on gram scales of substrate to furnish preparative amounts of oxidized products. A chemoinformatic analysis supports that Mn(CF 3 -PDP) significantly expands the pharmaceutical chemical space accessible to small-molecule C–H oxidation catalysis.

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Identification and optimisation of a novel series of pyrimidine based cyclooxygenase-2 (COX-2) inhibitors. Utilisation of a biotransformation approach

Cited by 19 publications

References 5 publications

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

PET imaging of cyclooxygenase-2 (COX-2) in a pre-clinical colorectal cancer model

A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C–H oxidation of carbocyclic N -heterocycles

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