Cyclooxygenase inhibitors containing

Dietary food supplement containing natural cyclooxygenase inhibitors and methods for inhibiting pain and inflammation... 

The structures of new potential cyclooxygenase (COX-2) inhibitors containing sila rings have been designed using theoretical methods (05MC215). 

LEUKOTRIENE RECEPTOR AGONISTS act at receptors recognizing leukotrienes and analogues. The lipoxygenase system forms the leukotrienes, which are members of the eicosanoid family of phospholipid mediators. Their name derives from the fact that leukotrienes are found in leucocytes and contain a triene system of double bonds. The other members of the eicosanoid family are the prostanoids (thromboxanes and the prostaglandins), and these are formed by the cyclooxygenase system see cyclooxygenase INHIBITORS. All the eicosanoids are derived mainly from arachidonic acid. These mediators are synthesized on demand, and in some cases their half-lives are short. The... 

Complexes of 5-alkylthio-l,2-dithiole-3-thiones 96 with cyclodextrins have been examined <05ARK(xii)47> and dithiolethiones such as 97 have been patented as cyclooxygenase inhibitors <05WOP51941>. The 1.2-ditellurole containing compound 98 and an anthracene analogue have been examined as the basis for molecular conductors... 

While comparatively few dihydrodiols have been observed in the metabolism of phenyl-containing drugs, the examples above are far from unique. Thus, oxazepam incubated in rat, mouse, and human microsomes did yield a dihydrodiol besides the para-phenol [82], A more-recent example is that of rofecoxib (10.22), a potent and selective cyclooxygenase-2 (COX-2) inhibitor. In rats and dogs, phenyl oxidation produced 4 -hydroxyrofecoxib and rof-ecoxib-3, 4 -dihydrodiol as urinary metabolites of intermediate quantitative importance [83]. 

Finally, NO has significant involvement in both acute and chronic inflammation. In acute inflammation, NO promotes swelling and increased vascular permeability. In animal models of acute inflammation, NOS inhibitors have a dose-dependent protective effect. In models of chronic inflammation (arthritis), NO is detrimental and L-arginine supplementation causes inflammatory exacerbation. At a molecular level, NO stimulates inflammation by activating the cyclooxygenase enzyme. Further supportive data are provided by the observation that fluid drained from the swollen joints of people with arthritis contains peroxynitrate and other oxidation products of NO. 

FIGURE 1 Structures of COX-1 and COX-2, (a) COX-1 with an NSAID inhibitor (flurbiprofen, orange) bound (PDB ID 3PGH). The enzyme consists of two identical monomers (gray and blue) each with three domains a membrane anchor consisting of four amphipathic helices a second domain that somewhat resembles a domain of the epidermal growth factor and the catalytic domain, which contains the cyclooxygenase and peroxidase activities, as well as the hydrophobic channel in which the substrate (arachidonate) binds. The heme that is part of the peroxidase active sites is shown in red ... 

Because of concerns about not detecting low concentrations of active compounds in such large mixtures, the current trend is toward much smaller mixtures containing only hundreds or even dozens of compounds. For example, the Affymax group prepared a library containing mixtures of only 540 compounds and identihed potent cyclooxygenase-1 inhibitors after deconvolution (34). The issue of optimum mixture size is not yet settled and discussion will no doubt continue for some time. 

Not many pyrazoles and indazoles exist in nature. However, many synthetic medicines do contain pyrazoles, pyrazolones, and indazoles. For instance, an anti-inflammatory cyclooxygenase-2 (COX-2) selective inhibitor celecoxib (Celebrex) has the tri-substituted pyrazole as its core structure. A fully substituted pyrazole, rimonabant (Acomplia), is a selective inverse agonist for the cannabinoid receptor type 1 (CBi). Acomplia was marketed in 56 countries for the treatment of obesity by Sanofi-Aventis starting in... 

---