A structural feature of N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulfonamide (NS-398) that governs its selectivity and affinity for cyclooxygenase 2 (COX2)

Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used because they alleviate pain, fever, and inflammation by inhibiting prostaglandin (PG) production by the enzyme cyclooxygenase (COX). A portion of the population experiences gastrointestinal side effects and nephrotoxicity during conventional NSAID 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 antiinflammatory therapy. In vitro screens revealed that nimesulide, 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, 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 cyclohexyl ring of NS-398 with different aliphatic groups of varying size, conformation and substitution.