Nonsteroidal anti inflammatory drugs (NSAIDs) are widely used because they alleviate pain, fever, and inflammation by inhibiting prostaglandin (PG) production by the enzyme cyclooxygenase (COX) . A port ion of the population experiences gastrointestinal side effects  and nephrotoxicity  during conventional N S A I D treatment. These afflictions are attributed to the inhibition of COX1, a constitutive form of COX, believed to be responsible for maintaining homeostatic levels of PG's in renal and gastrointestinal tissues . The recently discovered inducible form of this enzyme (COX2) is believed to augment prostaglandin production in inflammatory disease states . Therefore a program was established to seek therapeutically useful COX2 selective inhibitors which would not block PG production in gastric and renal tissues during anti inflammatory therapy. In vitro screens revealed that nimesulide (see Table), an antiinflammatory agent marketed outside the U.S., was a nonselective inhibitor of the recombinant murine COX1 (mCOX1) and COX2 (mCOX2) enzymes, while a close structural analog, NS-398 (see Table), was remarkably mCOX2 selective. We hypothesized that the molecular volume of the cyclohexyl ring of NS-398  may be important for its high affinity and COX2 selectivity. Consequently we explored the replacement of the cyclohexyt ring of NS-398 with different aliphatic groups of varying size, conformation and substitution.
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