Grosser, T., Fries, S. & FitzGerald, G. A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest. 116, 4-15

Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 02/2006; 116(1):4-15. DOI: 10.1172/JCI27291
Source: PubMed

ABSTRACT Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to minimize gastrointestinal complications of traditional NSAIDs--adverse effects attributed to suppression of COX-1-derived PGE2 and prostacyclin (PGI2). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2-derived PGI2 removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a "balance" between COX-2-derived PGI2 and COX-1-derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.

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    • "Inflammation is a physiological reaction which involves cellular and biochemical responses that cause symptoms for common diseases and even an early phase for some serious ailments such as Alzheimer's disease, cancer, heart vascular diseases (Fitzgerald, 2004; Grosser et al., 2006). Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketoprofen, ibuprofen and aceclofenac, which are currently in clinical use for the treatment of inflammatory disorders (Fitzgerald, 2004; Grosser et al., 2006), are associated with major drawbacks related to gastrointestinal disorders such as dyspepsia, gastric ulcers and so forth. These side effects are due to the direct contact of their free carboxylic groups with the gastric mucosa and due to decreased production of prostaglandins in the GIT (Fries and Grosser, 2005; Sauzem et al., 2008). "
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    ABSTRACT: Abstract In the presented study, we synthesized a novel series of 18 diphenylthiazole derivatives and tested their anti-inflammatory properties. They showed significant antiinflammatory properties in inflamed mice paws animal model. Docking-based analysis suggested that they act as COX enzyme inhibitors. The most potent compound 9e is significantly more active in reducing inflamed animal paws compared to diclofenac. Accordingly, we believe these compounds are good leads for further development into potent anti-inflammatory drugs.
    Medicinal Chemistry Research 07/2015; DOI:10.1007/s00044-015-1418-5 · 1.61 Impact Factor
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    • "COX-2, even if promotes the same AA biseoxygenation reaction, is mainly involved in inflammation and pain. The use of coxibs in humans allowed to unravel the protective role of COX-2 in the cardiovascular system mostly through the generation of prostacyclin [3]. COX-1 role in humans is quite vague except for platelet activation and gastrointestinal protection. "
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    ABSTRACT: Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a "lead" to design new isoxazoles (2a-m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a-m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure-activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran-2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC50 = 1.1 μM; COX-2 IC50 > 50 μM) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC50 = 0.58 μM). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket.
    European Journal of Medicinal Chemistry 01/2014; 74C:606-618. DOI:10.1016/j.ejmech.2013.12.023 · 3.43 Impact Factor
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    • "Unfortunate ly, many studies have identified an increased risk for cardiovascular events (Bresalier et al., 2005; Solomon et al., 2005) associate d with chronic use of COXib. The most plausible explanat ion for this effect is the suppression of COX-2-dependen t prostacycl in (Grosser et al., 2006 ), leaving unconstrained the intricate network of stimuli predisposin g to thrombos is, atheroge nesis, and hypertension, such as TXA2 (Rodriguez and Patrignani, 2006 ; Anzini et al., 2008 ). However , the withdrawal from the market of some COXib due to the increase of the risk of heart attack and cardiovascu lar side 0928-0987/$ -see front matter Ó 2013 Elsevier B.V. All rights reserved. "
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    ABSTRACT: Selective COX-2 inhibitors (COXib) belonging to the class of diaryl heterocycles (e.g., celecoxib, rofecoxib, etc.), are devoid of the undesirable effects due to their capacity to inhibit selectively inducible (COX-2), responsible for inflammatory effects but not constitutive cyclooxygenase-1 (COX-1)(COX); responsible for cytoprotective effects on gastric mucosa. In addition, several reports have identified an increased risk of cardiovascular events associated with the use of COXib. We have developed a new series of anti-inflammatory agents (1,5-diarylpyrrole-3-alkoxyethyl esters and ethers). To evaluate the effect of two 1,5-diarylpyrrole-3-alkoxyethyl ethers, VA441 and VA428 (up to 100μM), respectively, in comparison with two well known COXib, celecoxib and rofecoxib, on HaCaT cell (keratinocytes) proliferation and toxicity. Crucial molecules in cell cycle progression, i.e. NFκB and ERK as targets/mediators and cyclin D1 and p21 Cip1/Kip as final effectors were evaluated by Western blot, immunohystochemistry and RT-PCR analysis. Both compounds, VA441 and VA428, showed a strong inhibition of cell proliferation, and did not exhibit cytotoxicity. The anti-proliferative effect was accompanied by a strong activation of ERK and induction of the cell cycle inhibitor p21. In addition, there was a clear inhibition of the transcription factor NF-κB and downregulation of cyclin D1, with enforced inhibition of the HaCaT cell cycle progression. These data suggest that compounds VA441 and VA428, along with their role in inhibiting COX-2 and inflammation, could have a possible therapeutic (topical and systemic) use against skin proliferative disorders, such as psoriasis.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 02/2013; 49(2). DOI:10.1016/j.ejps.2013.02.009 · 3.01 Impact Factor
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