text: Early studies showed that, when inflammation is induced, the affected organ unexpectedly develops an enormous capacity to generate prostaglandins. It was demonstrated that the increase is due to de novo synthesis of fresh enzyme. In 1991, during the investigation of the expression of early-response genes in fibroblasts transformed with Rous sarcoma virus, a novel mRNA transcript that was similar, but not identical, to the seminal COX enzyme was identified. It was suggested that an isoenzyme of COX had been discovered. Another group discovered a novel cDNA species encoding a protein with similar structure to COX-1 while studying phorbol-ester-induced genes in Swiss 3T3 cells. The same laboratory showed that this gene truly expressed a novel COX enzyme. The two enzymes were renamed COX-1, referring to the original enzyme and COX-2.
  Building on those results, scientists started focusing on selective COX-2 inhibitors. Enormous effort was spent on the development of NSAIDs between the 1960s and 1980 so there were numerous pharmacophores to test when COX-2 was discovered. Early efforts focused on modification on two lead compounds, DuP-697 and NS-398. These compounds differ greatly from NSAIDs that are arylalkonic acid analogs. Encouraged by the "concept testing" experiments with selective inhibitors, and armed with several solid leads and clear idea of the nature of the binding site, development of this field was rapid. In vitro recombinant enzyme assays provided powerful means for assessing COX selectivity and potency and led to the discovery and clinical development of the first rationally designed COX-2 selective inhibitor, celecoxib. Efforts have been made to convert NSAIDs into selective COX-2 inhibitors such as indometacin by lengthening of the alkylcarboxylic acid side-chain, but none have been marketed.