Selective inhibition of cyclooxygenase 2.
Cyclooxygenase (COX), a key enzyme in the formation of prostanoids, is known to exist in two isoforms: an inducible enzyme (COX 2) and a constitutive from (COX 1). Both enzymes are inhibited by non-steroidal anti-inflammatory drugs (NSAID), but only marginal selectivity has thus far been reported. In this study, we report on a novel selective inhibitor of COX 2, CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanon e). Human washed platelets were used as a source of COX 1. For IL-1 stimulated rat mesangial cells we demonstrated the almost exclusive presence of COX 2 in western blot and mRNA analysis. Therefore these two model systems were chosen for selectivity testing. With an IC50 value of 15 nM, CGP 28238 blocked COX 2 activity in a similar concentration range to that of other potent NSAID such as indomethacin and diclofenac (IC50 = 1.17-8.9 nM). However, in contrast to these reference NSAIDs, CGP 28238 was at least 1000-fold less potent in inhibiting COX 1. Using other cell systems reported to express COX 1 or COX 2, we obtained a similar selectivity for COX 2. Thus, on the basis of our findings, CGP 28238 is a novel, highly potent and selective inhibitor of COX 2 and may be a lead compound for a new generation of potent anti-inflammatory drugs with an improved side-effect profile.
Klein
T
T
Faculty of Biology, University of Konstanz, F.R.G.
Nüsing
R M
RM
Pfeilschifter
J
J
Ullrich
V
V
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007189:Indans; D007527:Isoenzymes; D012333:RNA, Messenger; D011451:Prostaglandin-Endoperoxide Synthases; C059178:flosulide