Mechanistic studies on the selective inhibition of cyclooxygenase-2 by indanone derivatives.
The cyclooxygenase step in the conversion of arachidonic acid is a key point in the biosynthesis of prostanoids, managed by two enzymatic isoforms. In the following study we focused on the mechanism of the inhibitory action of CGP 28238 and structurally-related indanone derivatives using purified enzymes. Consistent with our earlier studies on cell systems, CGP 28238 revealed selective inhibition of cyclooxygenase-2. The process affects the bisoxygenase subunit time-dependently, and is reversible in the early phase of inhibition. From structure-activity relationships, we propose the formation of a Schiff base between the oxo-groups of CGP 28238 and an amino group at the active site providing additional binding forces for an effective inhibition of cyclooxygenase-2.
Klein
T
T
Faculty of Biology, University of Konstanz, FRG.
Nüsing
R M
RM
Wiesenberg-Boettcher
I
I
Ullrich
V
V
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000302:isolation & purification / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D013329:Structure-Activity Relationship
D016861:Cyclooxygenase Inhibitors; D007189:Indans; D007527:Isoenzymes; D011453:Prostaglandins; D016718:Arachidonic Acid; C013352:indacrinone; D011451:Prostaglandin-Endoperoxide Synthases; C059178:flosulide