|
Cyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane(s).〔Marnett, L. J. and A. S. Kalgutkar (1999). "Cyclooxygenase 2 inhibitors: discovery, selectivity and the future." Trends in Pharmacological Sciences 20(11): 465-469. 〕 Their main role is to catalyze the transformation of arachidonic acid into the intermediate prostaglandin H2, which is the procursor of a variety of prostanoids with diverse and potent biological actions.〔Mardini, I. A. and G. A. FitzGerald (2001). "Selective Inhibitors of Cyclooxygenase-2: A Growing Class of Anti-Inflammatory Drugs." Mol. Interv. 1(1): 30-38. ()〕 Cyclooxygenases have two main isoforms that are called COX-1 and COX-2 (as well as a COX-3). COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system. Prostaglandin synthesis in these sites is a key factor in the development of inflammation and hyperalgesia.〔Marnett, L. J. and A. S. Kalgutkar (1998). "Design of selective inhibitors of cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents." Current Opinion in Chemical Biology 2(4): 482-490. 〕 COX-2 inhibitors have analgesic and anti-inflammatory activity by blocking the transformation of arachidonic acid into prostaglandin H2 selectively.〔King, F. D., Ed. (2002). Medicinal chemistry Principles and practice. Cambridge, The royal Society of Chemistry.〕 ==The rise for development of selective COX-2 inhibitors== The impetus for development of selective COX-2 inhibitors was the adverse gastrointestinal side-effects of NSAIDs. Soon after the discovery of the mechanism of action of NSAIDs, strong indications emerged for alternative forms of COX, but little supporting evidence was found. COX enzyme proved to be difficult to purify and was not sequenced until 1988.〔Flower, R. J. (2003). "Case history: The development of COX-2 inhibitors." Nature Reviews Drug Discovery 2(3): 179. ()〕 But in 1991 the COX-2 enzyme was cloned and its existence, therefore, confirmed. Before the confirmed existence of COX-2, the Dupont company had developed a compound, DuP-697, that was potent in many anti-inflammatory assays but did not have the ulcerogenic effects of NSAIDs. Once the COX-2 enzyme was identified Dup-697 became the building-block for synthesis of COX-2 inhibitors. Celecoxib and rofecoxib, the first COX-2 inhibitors to reach market, were based on DuP-697.〔〔Dannhardt, G. and W. Kiefer (2001). "Cyclooxygenase inhibitors – current status and future prospects." European Journal of Medicinal Chemistry 36(2): 109-126. 〕 It took less than eight years to develop and market the first COX-2 inhibitor, with Celebrex (celecoxib) launched in December 1998 and Vioxx (rofecoxib) launched in May 1999.〔FDA, Center for Drug Evaluation and Research (2008). "FDA approved drug products – Celebrex." Retrieved 18.10., 2008, from ()〕〔FDA, Center for Drug Evaluation and Research (2008). "FDA approved drug products – Vioxx." Retrieved 18.10., 2008, from ()〕 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Discovery and development of cyclooxygenase 2 inhibitors」の詳細全文を読む スポンサード リンク
|