The discovery that the enzymatic conversion of arachidonic acid to prostaglandins (PGs) is catalyzed by two isoforms of cyclooxygenase (COX), but that only one isoform (COX-2) is pro-inflammatory, led to the hypothesis that selective inhibition of COX-2 will produce anti-inflammatory activity without adverse effects from inhibition of COX-1 (i.e., gastrointestinal toxicity and bleeding). The latter are the major clinical disadvantages of conventional nonsteroidal anti-inflammatory drugs (NSAIDs). A program to develop a selective COX-2 inhibitor was initiated with the goal of providing safer anti-inflammatory therapy; celecoxib was selected as the development candidate. The development of celecoxib provided important insights into the biology of COX, including: its role in inflammation and pain, the structure of the COX-2 active site, the basis of selective COX-2 inhibition, and strategies for making relevant assessments of COX-2 selectivity that supersede the limitations of in vitro enzyme assays.

Selective COX-2 inhibitors like celecoxib are distinguished from conventional (non-selective) NSAIDs by their novel interaction with a distinct region of the COX-2 active site which leads to highly potent and selective inhibition of that isoform. A hierarchy of evidence supporting celecoxib as COX-2 selective was obtained with in vitro assays using recombinant human COX isoforms, in vivo assays that assess PG concentrations as biomarkers of COX inhibition, long-term animal toxicology studies, and ultimately, clinical studies. Celecoxib exhibits potent oral anti-inflammatory and analgesic activity equal to naproxen and indomethacin in animal models of pain and inflammation, thus, its mechanism of action does not result in efficacy greater than that already seen with the more potent NSAIDs. More recent evidence suggests that the clinical usefulness of COX-2-selective agents may extend beyond inflammation and pain to the treatment of cancer and Alzheimer’s disease.