The development of COX2 inhibitors

Flower, Rod

doi:10.1038/nrd1034

Cited by 425 publications

(306 citation statements)

References 125 publications

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“…Expression of human COX-2 is very specific in certain tissues at basal level, and it is widely expressed in human endothelium (40) and human brain (41). During its absorption and distribution, orally taken aspirin can interact and acetylate endothelial COX-2, blocking prostacyclin biosynthesis (42,43).…”

Section: Figurementioning

confidence: 99%

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Pillai²,

Recchiuti³

et al. 2011

J. Clin. Invest.

258

305

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E-series resolvins are antiinflammatory and pro-resolving lipid mediators derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) that actively clear inflammation to promote tissue homeostasis. Aspirin, in addition to exerting antithrombotic actions, also triggers the biosynthesis of these specialized pro-resolving mediators. Here, we used metabolomic profiling to investigate the biosynthesis of E-series resolvins with specific chiral chemistry in serum from human subjects and present evidence for new 18S series resolvins. Aspirin increased endogenous formation of 18S-hydroxyeicosapentaenoate (18S-HEPE) compared with 18R-HEPE, a known resolvin precursor. Human recombinant 5-lipoxygenase used both enantiomers as substrates, and recombinant LTA 4 hydrolase (LTA4H) converted chiral 5S(6)-epoxide-containing intermediates to resolvin E1 and 18S-resolvin E1 (RvE1 and 18S-RvE1, respectively). 18S-RvE1 bound to the leukocyte GPCRs ChemR23 and BLT1 with increased affinity and potency compared with the R-epimer, but was more rapidly inactivated than RvE1 by dehydrogenase. Like RvE1, 18S-RvE1 enhanced macrophage phagocytosis of zymosan, E. coli, and apoptotic neutrophils and reduced both neutrophil infiltration and proinflammatory cytokines in murine peritonitis. These results demonstrate two parallel stereospecific pathways in the biosynthesis of E-series resolvins, 18R-and 18S-, which are antiinflammatory, pro-resolving, and non-phlogistic and may contribute to the beneficial actions of aspirin and ω-3 polyunsaturated fatty acids.

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Section: Figurementioning

confidence: 99%

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Pillai²,

Recchiuti³

et al. 2011

J. Clin. Invest.

258

305

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“…A large group of nonsteroidal anti-inflammatory drugs (NSAIDs) inhibiting both COX-1 and COX-2 isoforms followed. Only recently selective COX-2 inhibitors (Coxibs) have been developed (Flower, 2003). Here, we highlight a new strategy to inhibit COX-2 activity, focusing on the role of COX-2 in angiogenesis and in colorectal cancer (CRC).…”

mentioning

confidence: 99%

RNA interference as a key to knockdown overexpressed cyclooxygenase-2 gene in tumour cells

et al. 2006

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Silencing those genes that are overexpressed in cancer and contribute to the survival and progression of tumour cells is the aim of several researches. Cyclooxygenase-2 (COX-2) is one of the most intensively studied genes since it is overexpressed in most tumours, mainly in colon cancer. The use of specific COX-2 inhibitors to treat colon cancer has generated great enthusiasm. Yet, the side effects of some inhibitors emerging during long-term treatment have caused much concern. Genes silencing by RNA interference (RNAi) has led to new directions in the field of experimental oncology. In this study, we detected sequences directed against COX-2 mRNA, that potently downregulate COX-2 gene expression and inhibit phorbol 12-myristate 13-acetate-induced angiogenesis in vitro in a specific, nontoxic manner. Moreover, we found that the insertion of a specific cassette carrying anti-COX-2 short hairpin RNA sequence into a viral vector (pSUPER.retro) greatly increased silencing potency in a colon cancer cell line (HT29) without activating any interferon response. Phenotypically, COX-2 deficient HT29 cells showed a significant impairment of their in vitro malignant behaviour. Thus, the retroviral approach enhancing COX-2 knockdown, mediated by RNAi, proved to be an useful tool to better understand the role of COX-2 in colon cancer. Furthermore, the higher infection efficiency we observed in tumour cells, if compared to normal endothelial cells, may disclose the possibility to specifically treat tumour cells without impairing endothelial COX-2 activity.

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“…7,8 COX1 and COX2 are the two isoforms of cyclooxygenase in which the former is constitutively expressed in normal tissues to maintain homeostasis and latter is renowned to express on cytokine induction in inflammatory cells. 9 Unfortunately, during chronic inflammation, COX2 is overexpressed which leads to exaggerated way of immune response and ultimately results in developing proinflammatory diseases. 10 Copious efforts are underway to design the inhibitors against COX2 to treat these ailments.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2

Srinivas

Mohan

Baburajeev

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tIn the present study, we used solution combustion synthesis-bismuth oxide (Bi 2 O 3 ) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo [d]isoxazoles, 1-arylpiperazine and carbazoles ,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7 lM) over COX1 (40.4 lM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy.

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The development of COX2 inhibitors

Cited by 425 publications

References 125 publications

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

RNA interference as a key to knockdown overexpressed cyclooxygenase-2 gene in tumour cells

Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2

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