DESIGN OF SELECTIVE INHIBITORS OF CYCLOOXYGENASE-2 AS NONULCEROGENIC ANTIINFLAMMATORY AGENTS

The discovery of a second isoform of cyclooxygenase (cyclooxygenase-2) that is expressed in inflammatory cells and the central nervous syste m, but not in the gastric mucosa, offers the possibility of developing anti-inflammatory and analgesic agents that lack the gastrointestinal side effects of currently available nonsteroidal anti-inflammatory dr ugs. Lead compounds from several different structural classes have bee n identified and shown to be slow, tight-binding inhibitors that expre ss their selectivity for cyclooxygenase-2 in the time-dependent step. The determination of structures of enzyme-inhibitor cc-crystals along with site-directed mutagenesis experiments reveal the molecular basis for selectivity of some, but not all, inhibitors. Preclinical and clin ical studies suggest cyclooxygenase-2 inhibitors are highly promising new agents for the treatment of pain and inflammation, and for the pre vention of cancer.