Cyclooxygenases structure

Smith WL, Dewitt DL, Garavito MR Cyclooxygenases Structural, cellular, and molecular biology. Annu Rev Biochem 2000 69 145. [PMID 10966456]... 

Smith, WL, DeWitt, DL and Garavito, RM (2000) Cyclooxygenases structural, cellular, and molecnlar biology. Annu Rev Biochem, 69, 145-182. 

Both methods suggest that the chemical structure of A A (cis double bonds connected by two single bonds) allows the fatty acid to access the cyclooxygenase active site of PGHS-1 through a narrow hydrophobic channel and to bind in a shape favorable for the cyclooxygenation reaction. 

FIGURE 25.29 (a) The structures of several commou analgesic agents. Acetaminophen is marketed under the tradename Tylenol. Ibuprofen is sold as Motrin, Nuprin, and Advil, (b) Acetylsalicylate (aspirin) inhibits the cyclooxygenase activity of endoperoxide synthase via acetylation (covalent modification) of Ser ... 

In this bromoaspirin-inactivated structure, Ser , which lies along the wall of the tunnel, is bromoacetylated, and a molecule of salicylate is also bound in the tunnel. Deep in the tunnel, at the far end, lies Tyr, a catalytically important residue. Heme-dependent peroxidase activity is implicated in the formation of a proposed Tyr radical, which is required for cyclooxygenase activity. Aspirin and other NSAIDs block the synthesis of prostaglandins by filling and blocking the tunnel, preventing the migration of arachidonic acid to Tyr in the active site at the back of the tunnel. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Dewhirst FE. Structure/activity relationship for inhibition of prostaglandin cyclooxygenase by phenolic compounds. Prostaglandins 1980 20 209-222. 

The stems of the plant Perilla frutescens var. acuta have yielded two new prenyl 3-benzoxepine derivatives, perilloxin 53 and dehydroperilloxin 54, whose structures were established by spectroscopic means. An in vitro cyclooxygenase-1 bioassay was used to guide the separation of these natural products, which possessed moderate inhibitory activities against this enzyme (IC50 values for 53 and 54 were 23.2M and 30.4M respectively) <00JNP403>... 

D. Gildehaus, J. M. Miyashiro, T. D. Penning, K. Seibert, P. C. Isakson, and W. C. Stallings, Structural basis for selective inhibition of cyclooxygenase-2 by antiinflammatory agents, Nature 384 644 (1996). 

Chandrasekharan, N. V., Dai, H., Roos, K. L. et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs cloning, structure, and expression. Proc. Natl Acad. Sci. U.S.A. 99 13926-13931,2002. 

Compound 330 (Figure 31) is a potent and very selective cyclooxygenase-2 (COX-2) inhibitor <1997BMCL57>. Three-dimensional quantity-structure activity relationship (3-D QSAR) analysis of this compound and other members of a series of 5,6-diarylthiazolo[3,2-A][l,2,4]triazoles has been carried out <2004MI5>. 

Cyclooxygenase converts arachidonic acid first to prostaglandin G (PGG) and then to PGH prior to formation of prostaglandins, thromboxanes and prostacyclins. The structures of the intermediates and some of the end-products of these conversions are provided in Figure 11.28. 

Pak, J.Y. Gildehaus, D., Miyashiro, J.M., Penning, T.D., Seibert, K., Isakson, P.C., and Stallings, W.C. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature... 

The lability of benzylic positions to cytochrome P450 metabolism has been exploited to decrease the unacceptably low clearance and resultant long half-life of various compounds. For example celecoxib, a selective cyclooxygenase inhibitor, has a half-life of 3.5 h in the rat. Early structural leads, represented by compoimds in... 

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