Recent developments in cyclooxygenase inhibition.
Recent studies of the mechanism and selectivity of inhibition of cyclooxygenase enzymes are reviewed. The structural determinants of inhibition by the non-selective inhibitor, aspirin, and COX-2-selective diarylheterocycles are considered. Kinetic investigations indicate that the time-dependence of binding and inhibition of COX-1 and COX-2 by diarylheterocycles is more complex than originally postulated. The selectivity of inhibition is not determined by differences in the rates of association of the inhibitors with the two enzymes but rather by differences in the rates of dissociation. New strategies for the development of COX-2-selective inhibitors are highlighted.
Marnett
Lawrence J
LJ
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37215, USA. marnett@toxicology.mc.vanderbilt.edu
D001241:Aspirin / Q000378:metabolism; D001665:Binding Sites; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin