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Abstract
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.