Ibuprofen discovery

T Aspirin (acetylsalicylate Fig. 21-15b) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiinflammatory drug (NSAID Fig. 21-15c), inhibits the same enzyme. The recent discovery that there are two isozymes of COX has led to the development of more precisely targeted NSAIDs with fewer undesirable side effects (Box 21-2). 

With the variety of transformations that can be promoted by organopalladium reagents, it is unfortunate that palladium is such a rare metal. Biochemical processes might be much more exotic if palladium had been more abundant in the earth s crust at the origin of life (although selenium, which is an essential trace nutrient, is only approximately five times as concentrated as palladium in the earth s crust). The discovery of high turnover number catalysts has allowed several palladium-catalyzed reactions to be used in fine chemical and pharmaceutical synthesis. Naproxen (29) can be made using a Heck reaction. Ibuprofen s (30) synthesis... 

Ibuprofen possesses a stereogenic center, and studies have shown that (S)-ibuprofen is the active enantiomer. A chiral synthesis of (S)-ibuprofen, which is suitable for an industrial scale, has been developed by the Cheminor Company in India.111 Subsequent biochemical studies of racemic ibuprofen in mammalian tissue, however, have shown that there is an isomerase enzyme available in the body that can convert the / -enantiomer to (.S j-ibuprofen.112 Since this discovery, enthusiasm for the production of chiral ibuprofen has waned. Racemic ibuprofen is the only form of the drug that is currently readily available. 

In the 1960s, scientists discovered that aspirin acts by inhibiting cyclooxygenase (COX), a key enzyme in the conversion of arachidonic acid to prostaglandins (Section 19.5). With this discovery, it became clear why only one enantiomer of ibuprofen, naproxen, and ketoprofen is active Only the 5 enantiomer of each has the correct handedness to bind to COX and inhibit its activity. 

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