Comparative effects of selective cyclooxygenase 1 and cyclooxygenase 2 inhibitors on myeloperoxidase and 3 alpha-hydroxysteroid dehydrogenase.
The clinical efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is believed to result from the ability of these compounds to inhibit the inducible isoform of the enzyme cyclooxygenase, COX2. The gastrointestinal and renal side effects of these drugs, in contrast, are thought to relate to their ability to inhibit the constitutive isozyme, COX1. There is structural and pharmacological evidence that suggests that NSAIDs may also inhibit two unrelated enzymes, myeloperoxidase (MP) and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), potentially with untoward consequences for the patient. Our laboratories have been investigating a new structural class of potential COX inhibitors, the tri-cyclic aromatics. In this study we have examined the inhibitory potency of selected compounds for the enzymes human COX1, human COX2, human MP, and rat liver 3 alpha-HSD. The compounds selected span a range of COX isoform selectivities, from specific for COX2 to selective for COX1 only, and include three representative tri-cyclic aromatics. We found that compounds within the tri-cyclic aromatic class do not act as potent inhibitors of either myeloperoxidase or 3 alpha-HSD. These results demonstrate the unique inhibitor selectivity that can be achieved with the tri-cyclic aromatics. Examples of COX1 selective, and COX2 selective inhibitors within this structural class are presented.
Rider
N L
NL
DuPont Merck Research Laboratories, Wilmington, Delaware 19880-0400, USA.
Pinto
D
D
Covington
M
M
Orwat
M J
MJ
Giannaras
J
J
Nurnberg
S
S
Dowling
R
R
Davis
J P
JP
Williams
J M
JM
Trzaskos
J M
JM
Copeland
R A
RA
D015096:3-Hydroxysteroid Dehydrogenases / Q000187:drug effects*; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000494:pharmacology; D007213:Indomethacin / Q000031:analogs & derivatives / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology; D008565:Membrane Proteins; D009195:Peroxidase / Q000187:drug effects*; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011084:Polycyclic Aromatic Hydrocarbons; D011994:Recombinant Proteins; D015096:3-Hydroxysteroid Dehydrogenases; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen; D007213:Indomethacin