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 gastroi ntestinal and renal side effects of these drugs, in contrast, are thou ght to relate to their ability to inhibit the constitutive isozyme, CO X1. There is structural and pharmacological evidence that suggests tha t NSAIDs may also inhibit two unrelated enzymes, myeloperoxidase (MP) and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), potentially wi th untoward consequences for the patient. Our laboratories have been i nvestigating a new structural class of potential COX inhibitors, the t ri-cyclic aromatics. In this study we have examined the inhibitory pot ency of selected compounds for the enzymes human COX1, human COX2, hum an MP and rat liver 3 alpha-HSD. The compounds selected span a range o f COX isoform selectivities, from specific for COX2 to selective for C OX1 only, and include three representative tri-cyclic aromatics. We fi nd that compounds within the tri-cyclic aromatic class do not act as p otent inhibitors of either myeloperoxidase or 3 alpha-HSD. These resul ts demonstrate the unique inhibitor selectivity that can be achieved w ith the tri-cyclic aromatics. Examples of COX1 selective, and COX2 sel ective inhibitors within this structural class are presented.