Inhibitors of cyclooxygenase-2: November 1999-April 2000

Since the discovery of aspirin, the search for safer and more efficacious agents for the treatment of inflammation, pain and fever has continued for more than 3 century. Agents such as aspirin, the first synthetic NSAID, exert their effect by inhibiting the conversion of arachidonic acid to prostaglandins via the cyclooxygenase (COX) enzyme pathway. Beyond their therapeutic utility, traditional NSAIDs possess predictable side effects including dyspepsia, GI ulceration and antiplatelet activity. It is now well established that two isoforms of COX exist. COX-1 is constitutively formed and is responsible for production of basal. levels of prostaglandins needed for GI tract homeostasis, proper renal filtration rate and platelet aggregatory function. Biosynthesis of the COX-2 enzyme is induced by pro-inflammatory stimuli such as IL-l, TNF-a, growth factors and endotoxin LPS. The elevated levels of prostaglandins produced by the newly Formed COX-2 cause the pathologic symptoms of inflammation. Favourably, specific COX-2 inhibitors display efficacy as analgesic and anti-inflammatory agents without causing GI damage and antiplatelet activity demonstrated by traditional, non-selective NSAIDs. The decreased GI side effect profile may explain the rapid acceptance of the first two COX-2 inhibitors marketed, celecoxib and rofecoxib, which garnered over US$2 billion from their combined partial year of sales in 1999. COX-2 specific agents, due to their higher therapeutic index, can be studied at levels in excess of their therapeutic, anti-inflammatory dosage. Consequently, many new areas of research have become available. Pivotal preclinical and clinical research in the chemoprevention and treatment of cancer and the treatment of Alzheimer's disease is in progress. This review will cover the recent patent literature (November 1999 - April 2000) including new chemical classes and new filings on previously disclosed series.