A toxicologic and dermatologic assessment of salicylates when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

Design, synthesis, and biological evaluation of N-acetyl-2-carboxybenzenesulfonamides: a novel class of cyclooxygenase-2 (COX-2) inhibitors.

N-Acetyl-2-carboxybenzenesulfonamide (11), and a group of analogues possessing an appropriately substituted-phenyl substituent (4-F, 2,4-F(2), 4-SO(2)Me, 4-OCHMe(2)) attached to its C-4, or C-5 position, were synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 inhibition studies showed that 11 is a more potent inhibitor (COX-1 IC(50)=0.06microM; COX-2 IC(50)=0.25microM) than aspirin (COX-1 IC(50)=0.35microM; COX-2 IC(50)=2.4microM), and like aspirin [COX-2 selectivity index (S.I.)=0.14], 11 is a nonselective COX-2 inhibitor (COX-2 S.I.=0.23). Regioisomers having a 2,4-difluorophenyl substituent attached to the C-4 (COX-2 IC(50)=0.087microM; COX-2 S.I. >1149), or C-5 (COX-2 IC(50)=0.77microM, SI>130), position of 11 exhibited the most potent and selective COX-2 inhibitory activity relative to the reference drug celecoxib (COX-1 IC(50)=33.1microM; COX-2 IC(50)=0.07microM; COX-2 S.I.=472). N-Acetyl-2-carboxybenzenesulfonamide (11, ED(50)=49 mg/kg), and its C-4 2,4-difluorophenyl derivative (ED(50)=91 mg/kg), exhibited superior antiinflammatory activity (oral dosing) in a carrageenan-induced rat paw edema assay compared to aspirin (ED(50)=129 mg/kg). These latter compounds exhibited comparable analgesic activity to the reference drug diflunisal, and superior analgesic activity compared to aspirin, in a 4% NaCl-induced abdominal constriction assay. A molecular modeling (docking) study indicated that the SO(2)NHCOCH(3) substituent present in N-acetyl-2-carboxy-4-(2,4-fluorophenyl)benzenesulfonamide, like the acetoxy substituent in aspirin, is suitably positioned to acetylate the Ser(530) hydroxyl group in the COX-2 primary binding site. The results of this study indicate that the SO(2)NHCOCH(3) pharmacophore present in N-acetyl-2-carboxybenzenesulfonamides is a suitable bioisostere for the acetoxy (OCOMe) group in aspirin.

[Pharmacology and classification of cyclooxygenase inhibitors]. / Pharmacologie et classification des inhibiteurs de la cyclooxygénase.

The discovery of at least two cyclooxygenase (COX) isoenzymes had two major consequences: i) to give a new impetus to the research on lipid metabolism, giving rise to the crystallization of these peculiar membrane enzymes, the characterization of their active sites and their gene regulation, and the identification of new metabolic pathways; ii) the development of new NSAIDs aimed to have an improved safety profile, the coxibs. These drugs are defined by their COX-2 selectivity which is supported by a negligible inhibitory potency on platelet COX-1 in vitro and ex vivo after oral intake of maximal therapeutic doses. However, the coxibs marketed in France (celecoxib, rofecoxib, parecoxib) are not equivalent in terms of selectivity and some drugs developed by pharmaceutical companies (etoricoxib, lumiracoxib) will be even more selective for COX-2. These "new" coxibs are the final step in the theory of COX-2 selectivity and they will probably be helpful to better define the limitations of the therapeutic concept based on a selective inhibition of this iso-enzyme.

Design of acyclic triaryl olefins: a new class of potent and selective cyclooxygenase-2 (COX-2) inhibitors.

A new class of acyclic 1,1-diphenyl-2-(4-methylsulfonylphenyl)-2-alkyl-1-ethenes were synthesized, via a short two-step McMurry olefination reaction and then oxidation of the thiomethyl intermediate using Oxone, in 62-76% yield. The title compounds possess identical C-1 phenyl substituents which precludes the possibility of (Z)- and (E)-stereoisomers. 1,1-Diphenyl-2-(4-methylsulfonylphenyl)hex-1-ene exhibited highly potent (IC(50)=0.014 microM) and selective COX-2 (Selectivity Index >7142) inhibitory activity.

QSAR and classification models of a novel series of COX-2 selective inhibitors: 1,5-diarylimidazoles based on support vector machines.

The support vector machine, which is a novel algorithm from the machine learning community, was used to develop quantitation and classification models which can be used as a potential screening mechanism for a novel series of COX-2 selective inhibitors. Each compound was represented by calculated structural descriptors that encode constitutional, topological, geometrical, electrostatic, and quantum-chemical features. The heuristic method was then used to search the descriptor space and select the descriptors responsible for activity. Quantitative modelling results in a nonlinear, seven-descriptor model based on SVMs with root mean-square errors of 0.107 and 0.136 for training and prediction sets, respectively. The best classification results are found using SVMs: the accuracy for training and test sets is 91.2% and 88.2%, respectively. This paper proposes a new and effective method for drug design and screening.

Discovery of 2-phenyl-3-sulfonylphenyl-indole derivatives as a new class of selective COX-2 inhibitors.

2-Sulfonylphenyl-3-phenyl-indole derivatives have been reported to be highly potent and selective COX-2 inhibitors previously. In this paper, the regio-isomeric analogues-2-phenyl-3-sulfonylphenyl-indoles were identified as potent and selective COX-2 inhibitors. This work led to the discovery of compounds 4a and 8a possessing higher activity than Celecoxib on cellular assay.

Antinociception and the new COX inhibitors: research approaches and clinical perspectives.

New generations of cyclooxygenase (COX) inhibitors are more potent and efficacious than their traditional parent compounds. They are also safer than the classic non-steroidal anti-inflammatory drugs (NSAIDs) and are starting to be used not only for low to moderate intensity pain, but also for high intensity pain. Three different strategies have been followed to improve the pharmacological profile of COX inhibitors: 1. Development of COX-2 selective inhibitors. This is based on the initial hypothesis that considered COX-2 as the enzyme responsible for the generation of prostaglandins only in inflammation, and, therefore, uniquely responsible for inflammation, pain and fever. Initial expectations gave rise to controversial results, still under discussion. The second generation of these compounds is being developed and should contribute to clarifying both their efficacy and the specific functions of the COX enzymes. 2. Modified non-selective COX inhibitors. Molecules like nitro-NSAIDs or tromethamine salt derivatives have been synthesized considering that both COX-1 and COX-2 are responsible for the synthesis of prostaglandins involved either in homeostatic functions or inflammation. Nitroaspirin, nitroparacetamol or dexketoprofen trometamol are some examples of molecules that are already showing an important clinical efficacy. The modifications performed in their structures seem to lower the unwanted side effects as well as to enhance their analgesic efficacy. 3. Combined therapy of classic NSAIDs with other drugs. This strategy looks for improvements in the incidence of adverse effects or to take advantage of the synergistic enhancement of their therapeutic effects. Some of the molecules resulting from these strategies are very valuable as therapeutic agents and open a wide range of possibilities in the treatment of high intensity pain, including neuropathic pain, and opiate sparing therapy.

Cyclo-oxygenase inhibition in colorectal adenomas and cancer.

Increasing evidence indicates that Non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), can reduce the number and size of adenomas in patients with familial adenomatous polyposis as well as the incidence of colorectal cancer. The COX enzyme family consists of the classic COX-1 and a second enzyme, COX-2, which is induced by various stimuli, such as mitogens and cytokines. While it is well proven that COX-2 overexpression is a central event in colorectal carcinogenesis, that prostaglandins (PGs) can contribute to tumorigenesis, and that COX-2 selective inhibitors are active chemopreventive agents, the molecular mechanisms by which NSAIDs exert their chemopreventive effect is not fully understood. However, significant advances have been made in understanding the interference of NSAIDs with the pathways that control cell growth and survival even independently from their COX-inhibiting properties, making their use attractive both alone and in combination with standard therapies in the treatment of advanced colorectal cancer. In addition, the recently recognized anti-angiogenic and radiosensitizer properties of COX-2 inhibitors support, further suggest their use in the adjuvant setting.

Cyclo-oxygenase 2 inhibitors: an important new drug classification.

The pharmacologic treatment of acute and chronic pain has evolved greatly over the last several decades. Notably, several new classifications of drugs have emerged to meet the growing demand of patients in pain and health care providers who attempt to assist them. This article describes 1 new classification, cyclo-oxygenase 2 inhibitors, and provides specifics about the 2 agents currently available via prescription.

[Non-steroidal anti-inflammatory agents with selective inhibitory activity on cyclooxygenase-2. Interest and future prospects]. / Les anti-inflammatoires non stéroïdiens inhibiteurs sélectifs de la cyclooxygénase. 2. Intérêt et perspectives.

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of primary prostanoids by blocking the access of arachidonic acid to the active site of the cyclooxygenases (COXs). Because the prostanoids produced by COX-1 appear to play a physiological role (protection of the gastric mucosa, platelet aggregation, vascular homeostasis, maintenance of renal sodium-water balance) while those produced by COX-2 seem mainly to intervene in the inflammatory response and in certain processes associated with cell proliferation, the hypothesis has been put forward that the NSAIDs that are selective COX-2 inhibitors should theoretically be capable of maintaining NSAID therapeutic properties but also have fewer adverse side effects due to the maintenance of prostaglandin production at normal physiological levels. CURRENT KNOWLEDGE AND KEY POINTS: The hypothesis of COX isoenzyme selectivity has led to a proposed classification for COX inhibitors: 1) COX-1 selective inhibitors (low-dosage aspirin); 2) COX non-selective inhibitors (the majority of classified NSAIDs, which when administered over the long term, e.g., in cases of rheumatoid arthritis, cause duodenal ulcers in 20% of cases and gastric hemorrhage in 1-4% of cases/year); 3) COX-2 preferential inhibitors (meloxicam and nimesulide, which have fewer gastric side effects than standard NSAIDs, but which are not risk-free at high doses); 4) COX-2 selective inhibitors (celecoxib and rofecoxib). Preliminary clinical studies have shown that COX-2 selective inhibitors are as efficient as standard NSAIDs and have fewer adverse digestive side effects, thereby confirming the interest of this proposed classification. In the UK, the aforementioned studies have led to the commercialization of rofecoxib for the treatment of pain and osteoarthritis, while celecoxib has been introduced in medical practice in the USA and other countries for the treatment of rheumatoid arthritis and osteoarthritis. FUTURE PROSPECTS AND PROJECTS: Various epidemiological and laboratory studies have indicated that NSAIDs may be able to reduce the risk of cancer (colorectal cancer in particular) and Alzheimer's disease due to their inhibitory activity on COXs, especially COX-2. The therapeutic contribution of COX-2 specific inhibitors has to be more fully evaluated, particularly as these agents could delay the healing of duodenal ulcers and interfere with several COX-2-induced physiological functions. It is therefore suggested that until further information becomes available, this new class of NSAIDs should be used with caution in certain patient populations.

Defining COX-2 inhibitors.

Arachidonic acid metabolism is governed by 2 isoforms of cyclooxygenase (COX), the constitutively expressed COX-1 and the inducible COX-2. Antiinflammatory, analgesic, and antipyretic effects of nonsteroidal antiinflammatory drugs (NSAID) are explained by the capacity of these agents to inhibit COX-2, whereas the serious gastrointestinal side effects are caused by inhibitors of COX-1. The first of a new class of COX inhibitors, the COX-2 specific inhibitors, has just been approved for the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA). As the clinical outcomes of specific COX-2 inhibitors are considerably different than those of NSAID, it is essential for the clinician to understand the basis of classification of those new, effective, and safer therapeutic agents for the treatment of OA and RA.