First and Second Generations of COX-2 Selective Inhibitors

Leval, Xavier de; Julémont, Fabien; Benoît, Valérie; Frédérich, Michel; Pirotte, Bernard; Dogné, Jean‐Michel

doi:10.2174/1389557043403693

Cited by 23 publications

(14 citation statements)

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“…Prostanoids deriving from COX-1 play important roles in homeostatic processes such as thrombogenesis and homeostasis of the gastrointestinal tract and kidneys. Conversely, COX-2 is expressed in pathological conditions such as *Address correspondence to this author at the University of Namur, Drug Design and Discovery Center, Department of Pharmacy, 61 rue de Bruxelles, 5000 Namur, Belgium; Tel: 0032 (0)81724289; Fax: 0032 (0)81724299; E-mail: jean-michel.dogne@fundp.ac.be The first two authors have contributed equally to this work inflammation or cancer proliferation [1,2]. COX-2 expression is also observed in some tissues such as vascular endothelium, kidney or brain under normal conditions, suggesting the involvement of COX-2 in the regulation of physiological processes [3].…”

Section: Cyclooxygenase Inhibitionmentioning

confidence: 99%

“…However, all those drugs cause untoward side-effects related to COX-1 inhibition of which the most prevalent ones are represented by gastrointestinal irritation [1]. The identification and characterization of COX-2 in inflammatory cells was the start of the development of more selective NSAIDs, with reduced side-effects (essentially gastro-intestinal toxicity) compared to classical NSAIDs.…”

Section: Cyclooxygenase Inhibitionmentioning

confidence: 99%

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Dual Carbonic Anhydrase - Cyclooxygenase-2 Inhibitors

Dogné¹,

Thiry²,

Praticò³

et al. 2007

CTMC

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Cyclooxygenase is a key enzyme responsible for metabolisation of arachidonic acid into prostaglandins and thromboxane. This enzyme is the target of non steroidal anti-inflammatory drugs (NSAIDs), used against inflammation and pain. The inducible COX-2 was associated with inflammatory conditions, whereas the constitutive form (COX-1) was responsible for the beneficial effects of the PGs. This observation led to the development of COX-2 inhibitors or "coxibs" of which rofecoxib (Vioxx) characterized by a methylsulfone moiety and the sulfonamides celecoxib (Celebrex) and valdecoxib (Bextra). Initially described as COX-2 "selective" inhibitors, recent reports revealed a nanomolar inhibition activity of the sulfonamide COX-2 inhibitors for several carbonic anhydrase (CA) isoforms, confirmed by X-ray crystal structures for the adducts of celecoxib and valdecoxib with isozyme CA II. This dual activity may help to explain differences in clinical observation between sulfonamide and methylsulfone COX-2 inhibitors. Moreover, the inhibition of CA isozymes, critical for the development and invasion of cancer cells, such as CA II, IX and XII, may constitute an important mechanism of antitumor action of such sulfonamide compounds.

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Section: Cyclooxygenase Inhibitionmentioning

confidence: 99%

Section: Cyclooxygenase Inhibitionmentioning

confidence: 99%

Dual Carbonic Anhydrase - Cyclooxygenase-2 Inhibitors

Dogné¹,

Thiry²,

Praticò³

et al. 2007

CTMC

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“…[23][24][25][26] The advantage of inhibiting selectively COX-2, an enzyme that is mainly induced as a result of an inflammatory stimulus, is that it will not inadvertently block the beneficial prostanoids that are produced by COX-1. 10,27,28 The induced COX-2 enzyme was thought to generate excessive amounts of detrimental prostanoids at sites of injury, thereby amplifying the damage and overwhelming local host defense mechanisms. Although this simple concept is generally true, exceptions have become apparent as a result of the clinical use of selective COX-2 inhibitors.…”

Section: Chimeric Cyclooxygenase-2 Inhibitorsmentioning

confidence: 99%

Frontiers in Nephrology

Letts¹,

Loscalzo

2007

Journal of the American Society of Nephrology

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“…Deregulation of the COX-2 pathway appears to affect tumorigenesis via a number of distinct mechanisms: promoting tumour maintenance and progression, favoring metastatic spread, and perhaps even participating in tumour initiation [7]. As such, COX-2-selective inhibitors typified by rofecoxib, celecoxib and valdecoxib [8] were developed to reduce the incidence of gastrointestinal side effects associated with non-selective long-term inhibition of COX-1 and COX-2 by traditional NSAIDs.…”

Section: Introductionmentioning

confidence: 99%

A novel nitro-oxy substituted analogue of rofecoxib reduces human colon cancer cell growth

et al. 2011

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Rofecoxib is a specific COX-2 inhibitor able to exert antiproliferative activity against colorectal cancer cells. It was withdrawn from the market after the demonstration of an increased risk of cardiovascular complications after prolonged use. Nevertheless it remains an interesting compound for laboratory research as an experimental COX-2 inhibitor. In the present study the antiproliferative activity of a novel dinitro-oxy-substituted analogue of rofecoxib (NO-rofe), potentially less cardiotoxic, has been investigated in vitro on human colon cancer cells and compared with the action of the parent drug. Due to the fact that COX-2 inhibition is the main characteristic of coxibs we performed all experiments in COX-2-overexpressing (HT-29) and COX-2-negative (SW-480) human colon cancer cells, in order to elucidate whether the observed effects were dependent on COX-2 inhibition. Moreover, experiments were performed in order to evaluate whether COX-2 pharmacological inhibition may affect beta-catenin/E-cadherin signalling pathway.NO-rofe exerted a significant antiproliferative activity on COX-2 positive HT-29 human colon cancer cells, being less effective on the COX-2 negative SW-480 human colon cancer cell line. In particular, the rofecoxib analogue retained similar potencies with respect to COX-2 inhibition but was much more active than rofecoxib in inhibiting the growth of human colon cancer cells in vitro.In addition, this novel compound resulted in the induction of membrane β-catenin/E-cadherin expression, a feature that may significantly contribute to its antiproliferative activity.

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First and Second Generations of COX-2 Selective Inhibitors

Cited by 23 publications

References 0 publications

Dual Carbonic Anhydrase - Cyclooxygenase-2 Inhibitors

Dual Carbonic Anhydrase - Cyclooxygenase-2 Inhibitors

Frontiers in Nephrology

A novel nitro-oxy substituted analogue of rofecoxib reduces human colon cancer cell growth

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