Current Status of COX-2 Inhibitors

Singh, Palwinder; Mittal, Anu

doi:10.2174/138955708783331577

Cited by 54 publications

(31 citation statements)

References 59 publications

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“…Inflammation is the main etyological factor in oral squamous cell carcinoma (OSCC), COX-2 activity is related both to inflammation and carcinogenesis and its expression has been found increased in OSCC together with other pro-inflammatory molecules as inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF); overexpression of these markers was also associated with limph node metastasis, tumor staging and grading [25][26].…”

Section: Discussionmentioning

confidence: 99%

Expression of cyclooxygenase-1 and cyclooxygenase-2 in normal and pathological human oral mucosa.

Mauro

Lipari²,

Leone

et al. 2011

Folia Histochem Cytobiol.

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Cyclooxigenase (COX) is the rate-limiting enzyme for the conversion of arachidonic acid (AA) to prostaglandins (PGs). Two isoforms of COX have been identified: COX-1 is constitutively expressed in many cells and is involved in cell homeostasis, angiogenesis and cell-cell signalling; COX-2 is not expressed in normal condition however it is strongly expressed in inflammation. The oral cavity is costantly exposed to physical and chemical trauma that could lead to mucosal reactions such as hyperplasia, dysplasia and cancer. Early diagnosis is the most important issue to address for a positive outcome of oral cancer; therefore it would be useful to identify molecular markers whose expression is associated with the various stages of oral cancer progression. Since COX enzyme has been involved, with different mechanisms, in the development and progression of malignancies we decided to investigate the expression and localization of COX-1 and COX-2 in normal human oral mucosa and three different pathologies (hyperplasia, dysplasia and carcinoma) by immunohistochemistry and RT-PCR. COX-1 mRNA and protein have been detected already in normal oral mucosa and their expression progressively increases from normal samples towards hyperplasia, dysplasia and finally carcinoma. On the contrary, COX-2 is not expressed in the normal tissue, starts to be expressed in hyperplasia, reaches the maximum activation in dysplasia and then starts to be downregulated in carcinoma.

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Section: Discussionmentioning

confidence: 99%

Expression of cyclooxygenase-1 and cyclooxygenase-2 in normal and pathological human oral mucosa.

Mauro

Lipari²,

Leone

et al. 2011

Folia Histochem Cytobiol.

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“…19) Most of them have high lipophilicity. Indomethacin is a traditional non-selective inhibitor of the COX isozyme which is widely used as a NSAID, but with poor brain penetration largely due to the presence of the carboxylic acid moiety.…”

Section: )mentioning

confidence: 99%

11C-Labeled Analogs of Indomethacin Esters and Amides for Brain Cyclooxygenase-2 Imaging: Radiosynthesis, in Vitro Evaluation and in Vivo Characteristics in Mice

Yamamoto

Toyohara

Ishiwata

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Cyclooxygenase (COX) is the crucial enzyme in the conversion of arachidonic acid to prostaglandins. It exists at least in two isoforms, a constitutive form (COX-1) and an inducible form (COX-2), 1-3) although a third distinct COX isozyme has also been reported.4) The COX-1 enzyme is responsible for maintaining homeostasis whereas COX-2 is induced during inflammation by various stimuli and, in some tissues including the brain, kidney and placenta, is also constitutively expressed. Recent studies indicate that elevated expression of COX-2 has been implicated in many pathological events, including rheumatoid arthritis, cancer, heart disease, and neurodegenerative disorders. 5)In the brain, COX-2 is mainly expressed in the cortex, hypothalamus, and hippocampus, 6) and is upregulated in neurological disorders such as Parkinson's disease and Alzheimer's disease, [7][8][9] although the functions of COX-2 in pathophysiological processes are not yet well-understood. There is great potential that COX-2-targeted imaging by positron emission tomography (PET) may provide useful information on the role of this enzyme, especially in various neurological disorders, and also may help to evaluate the efficacy of selective COX-2 inhibitors. 10) Thus, many COX-2 inhibitors have been labeled with a suitable radionuclide for mapping the enzymes in vivo. However, previously evaluated PET radiotracers, including 11 C-labeled COX inhibitors of the diarylheterocyclic class which were synthesized by us, 11,12) have only achieved limited success, due to a lack of sufficient specific-binding to the COX-2 enzyme and/or sufficient brain penetration, in spite of promising in vitro pharmacological data. [13][14][15][16][17][18] There is a need for systematic studies correlating the physicochemical properties of agents with their in vivo behavior for a better design of COX-2 imaging probes.Currently, many selective COX-2 inhibitors with various structural features, as exemplified by vicinal diaryl heterocycles such as celecoxib and refecoxib, have been developed as non-steroidal anti-inflammatory drugs (NSAIDs) with improved gastric safety profiles.19) Most of them have high lipophilicity. Indomethacin is a traditional non-selective inhibitor of the COX isozyme which is widely used as a NSAID, but with poor brain penetration largely due to the presence of the carboxylic acid moiety. 20) Interestingly, recent studies concerning ester and amide derivatives of indomethacin have found very high COX-2 inhibition potency and a high degree of COX-2-selectivity.21-23) Marnett and colleagues synthesized 123 I-labeled N-iodobenzyl-containing amide derivative of indomethacin as a COX-2 imaging agent, which exhibited sufficient stability in COX-2 expressing nude mouse tumor.24) More recently, using organic fluorophores tethered to indomethacin through an amide linkage, the feasibility of specific in vivo targeting of COX-2 in inflammatory lesions in mice has been demonstrated by the same group. 25)The purpose of this study is to find suitable radioligands ...

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“…The discovery of the speciic role of COX-2 enzyme in inlammation resulted in the development of several COX-2 selective inhibitors to overcome the GI side efects of classical NSAIDs [15,16]. Interestingly, before the conirmation of existence of COX-2 enzyme, the DuPont company discovered a compound Dup-697 (Figure 2) as a potent anti-inlammatory agent without having the ulcerogenic efects of NSAIDs [17].…”

Section: Progress In the Pursuit Of The Development Of Cyclooxygenasementioning

confidence: 99%

“…Furthermore, recent studies revealed the association of COX-2 with various other pathophysiological processes such as Alzheimer's disease, Parkinson disease, schizophrenia, epilepsy, depression, diabetic peripheral neuropathy and various cancers. [15,16]. The recognition of new roles for COX-2 selective inhibitors imposed a great challenge to the researchers to design and explore alternative scafolds to develop COX-2 selective inhibitors with improved potency and eicacy in order to circumvent various side efects associated with the currently available NSAIDs.…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis of Binding Interactions of NSAIDs and Computer-Aided Drug Design Approaches in the Pursuit of the Development of Cyclooxygenase-2 (COX-2) Selective Inhibitors

Deb¹,

Mailabaram²,

Al-Jaidi³

et al. 2017

Nonsteroidal Anti-Inflammatory Drugs

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The nonsteroidal anti-inlammatory drugs (NSAIDs) are important class of therapeutic agents used for the treatment of pain, inlammation and fever. Nonselective inhibition of cyclooxygenase (COX-1 and COX-2) isoenzymes by classical NSAIDs is associated with undesirable side efects such as gastrointestinal (GI) and renal toxicities due to COX-1 inhibition. To circumvent this problem, several COX-2 selective inhibitors were developed with superior GI safety proile. However, the voluntary market withdrawal of potent COX-2 selective inhibitors (rofecoxib and valdecoxib) due to their severe cardiovascular toxicity which is also found to be associated with some of the traditional NSAIDs suggesting the need to relook into the entire class of NSAIDs rather than exclusively victimizing the COX-2 selective inhibitors. Furthermore, the recent evidences for the involvement of COX-2 selective inhibitors in the aetiology of many diseases, such as Alzheimer's disease, Parkinson's disease, diabetes, various cancers and so on, have gained much atention for researchers to design and develop novel COX-2 selective inhibitors with improved pharmacodynamics and pharmacokinetic proile. This chapter is focused on the detailed analysis of molecular basis of binding interactions of various NSAIDs by highlighting the role of crucial amino acid residues at the binding site of cyclooxygenase enzymes (COXs) to be considered for selective inhibition of COX-2 enzyme while emphasising the impact of signiicant CADD strategies employed for designing new potent COX-2 inhibitors with tuned selectivity.

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Current Status of COX-2 Inhibitors

Cited by 54 publications

References 59 publications

Expression of cyclooxygenase-1 and cyclooxygenase-2 in normal and pathological human oral mucosa.

Expression of cyclooxygenase-1 and cyclooxygenase-2 in normal and pathological human oral mucosa.

11C-Labeled Analogs of Indomethacin Esters and Amides for Brain Cyclooxygenase-2 Imaging: Radiosynthesis, in Vitro Evaluation and in Vivo Characteristics in Mice

Molecular Basis of Binding Interactions of NSAIDs and Computer-Aided Drug Design Approaches in the Pursuit of the Development of Cyclooxygenase-2 (COX-2) Selective Inhibitors

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