Selective cyclooxygenase-2 inhibitors as non-ulcerogenic anti-inflammatory agents

The recent discovery of the second isozyme of cyclooxygenase (cyclooxygenase-2, COX-2), expressed in response to inflammatory stimuli and present in the central nervous system, but not in the gastric mucosa, provides a unique opportunity to develop non-steroidal anti-inflammatory drugs (NSAIDs) which lack the ulcerogenic liabilities associated with currently marketed drugs. Discovery efforts towards the identification of selective COX-2 inhibitors have led to an impressive array of lead compounds, most of which display potent COX-2 inhibition with little or no effect on COX-1 activity. Most COX-2-selective inhibitors behave as slow, tight-binding inhibitors and display their selectivity in the time-dependent step. Examination of the enzyme-inhibitor co-crystal structures reveals the structural basis of some, but not all inhibitors. Preclinical and clinical trials have demonstrated the efficacy of COX-2 inhibitors as safe anti-inflammatory and analgesic agents. In addition, animal and epidemiological studies suggest potential applications of these compounds in cancer chemoprevention and Alzheimer's disease. In the present review, novel structural classes and modifications of existing compounds, including NSAIDs, are discussed with special emphasis on their molecular and structural basis for selective COX-2 inhibition.