Structural and functional basis of cyclooxygenase inhibition.

Brief History. The use of medicinal substances for the treatment of pain and fever dates to ancient Egyptian and Grecian civilizations, where dried myrtle leaves or bitter extracts from the bark of poplar trees were used to treat back and abdominal pain. The Ebers papyrus from ancient Egypt (1850 B.C.) is the oldest preserved medical text and contains the first record documenting the use of plant remedies for the treatment of pain and inflammation. Other records show that in 400 B.C., Hippocrates prescribed the bark and leaves of the willow tree to reduce fever and to relieve the pain of childbirth. The first published report documenting the antipyretic and analgesic properties of willow bark appeared in England in 1763 in a presentation to the Royal Society by Reverend Edward Stone.1 The active component of willow bark was later identified as salicin, which is metabolized to salicylate. In 1832, the French chemist Charles Gerhardt experimented with salicin, generating salicylic acid, and in 1860 Kolbe and Lautemann developed a highly efficient method for the synthesis of salicylic acid from phenol, which led to the use of the compound in the general population as an antiseptic and antipyretic. In 1897, Felix Hoffman from the Bayer Company developed a more palatable form of salicylate by synthesizing acetylsalicylic acid, which was called “aspirin” and distributed by Bayer in tablet and powder form in 1899. In the decades that followed, other compounds that possessed similar antipyretic, analgesic, and antiinflammatory properties (phenylbutazone (4butyl-1,2-diphenylpyrazolidine-3,5-dione), 1949, and indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3acetic acid), 1963) were developed, although the mechanism of action was unknown. In 1971, John Vane showed that aspirin, indomethacin, and sodium salicylate all cause a dose-dependent decrease in the synthesis of prostaglandins from cell-free homogenates of lung tissue.2 Vane was awarded the Nobel Prize in physiology and medicine in 1982, in conjunction with Sune Bergstrom and Bengt Samuelson, for “discoveries on prostaglandins and related biologically active substances”. Vane,2,3 concurrent with Smith and Willis,4 proposed that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDsa) inhibited the enzyme activity that converts polyunsaturated fatty acids to prostaglandins during the inflammatory process. The prostaglandin endoperoxide synthase or fatty acid cyclooxygenase (COX) that catalyzes the dioxygenation of arachidonic acid (AA) to form prostaglandin H2 (PGH2) and the resultant prostaglandins was first characterized in detail in 1967 using preparations from sheep seminal vesicles.5 A purified and enzymatically active COX was isolated in 1976,6 and the existence of two COX isoforms (encoded by distinct genes) with high amino acid sequence homology (60%) but differential expression profiles was reported in 1991.7,8 Both COX isoforms are bifunctional, membrane-bound enzymes located on the lumenal surfaces of the endoplasmic reticulum and on the inner and outer membranes of the nuclear envelope.9 Found in most tissues, COX-1 is the constitutively expressed isoform and is involved in the production of prostaglandins that mediate basic housekeeping functions in the body. Although COX-2 is