Discovery of the Classical Non-steroidal Anti-inflammatory Drugs

8 Discovery of the Classical Non-steroidal Anti-inflammatory Drugs 

The standard therapy for rheumatoid arthritis relyed in the 1950s on corticosteroids, in spite of their massive side-effects (Fig. 5.82). The single nonsteroidal substance, which was known in the 1950s and could help in relief of rheumatoid arthritis, was Aspirin . But due to the associated serious risk of damaging the gastric mucosa at elevated doses, it could not be used for longterm application. 

Stewart Adams and John Nicholson at the Boots Company in Nottingham took acetylsalicylic acid as a lead template and looked for related anti-inflammatory structures, which would be devoid of the ASA-related side-effect. In 1955, they discovered that their anti-inflammatory compounds reduced skinreddening (erythema) in guinea-pigs, caused by ultraviolet irradiation. Thereby they had foimd a simple and feasible assay system to test a whole host of compounds. In 1961, out of a group of several hundred substances they were able to select the one, which was introduced to the British market in 1969 under the name ofibuprofen (Fig. 5.83). [180] 

Also other members of the profen-family, among them naproxen, flurbiprofen, ketoprofen and tiaprofenic acid, are of great importance today. In general, these are 2-aryl- or 2-heteroaryl-propionic acids, of which in vitro only the (S)-(+)-enantiomer inhibits cyclooxygenase-1 (Fig. 5.84). In vivo, depending on the particular animal species, and also in humans, the (U)-(-)-enantiomer is converted to various degrees into its (S)-enantiomer with the aid of -methylacyl-CoA-racemase, via the Coenzyme A-thioester. In addition, more recent investigations could show that (R)-ibuprofen and (R)-flurbiprofen themselves have also anti-inflammatory properties. Many of the profens, with the exception of naproxen, are therefore marketed as racemates. 

Several drug companies have developed, apart from profens, additional classes of NSAIDs (Fig. 5.85). Many of these compounds, like the profens and acetylsalicylic acid, as well as the natural prototype, arachidonic acid, possess as 

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