Nonsteroidal Anti-Inflammatory Drugs – Ibuprofen
After World War II, thanks to aspirin’s tremendous commercial success, drug firms began to look for super-aspirins—anti-inflammatory drugs with better potency but fewer side effects. Four companies made significant contributions to the field at the time: Geigy in Switzerland, Parke-Davis and Merck in the United States, and Boots in the United Kingdom. At that time, animal models were becoming more and more important, because the old-fashioned way in which scientists made and ingested compounds themselves was no longer viable. Not only was using human guinea pigs out of fashion, but also compounds were being systematically made in greater numbers.
Charles Winter at Merck, Sharp, and Dohme (he later moved to Parke-Davis) developed the cotton string granuloma test as a model of inflammatory pain. Using this model, Merck screened about 350 indole compounds and identified indomethacin as a potent anti-inflammatory drug. In-domethacin was initially synthesized by medicinal chemist T. Y. Shen (who later became vice president of inflammation research at Merck) as a plant growth regulator. It was also found to be particularly active in another model of inflammatory pain, carrageenan-induced rat paw edema. Indomethacin was introduced in 1964 and is still regarded as a gold standard that combines both anti-inflammatory and analgesic activity. In all, Merck synthesized more than 500 salicylate compounds that led eventually to diflunisal (Dolobid), a 5-fluorophenyl salicylate, in 1971.
In 1949, pharmacologist Gerhard Wilhelmi at Geigy in Basel developed a novel animal model for inflammation. His method measured edema elicited in the depilated skin of guinea pigs following irradiation with ultraviolet (UV) light. Wilhelmi published his method in 1950. Geigy identified phenylbutazone as a particularly active anti-inflammatory drug, using Wilhelmi’s UV erythema model. The commercial success of phenylbutazone, in turn, catalyzed the merger between Geigy and Ciba. Ultimately, Ciba Geigy merged with Sandoz to form today’s Novartis.
At the end of 1958, a paper published by Steve Winder of Parke-Davis reported that he had developed a UV erythema technique for screening anti-inflammatory drugs. Winder’s model was similar to, and likely inspired by, Wilhelmi’s model. Using this model, Parke-Davis successfully identified a group of fenamates, which also became a commercial success.
Coincidentally, pharmacologist Stewart S. Adams at Boots in the United Kingdom was taking a similar approach. After obtaining his Ph.D. in 1952 at the University of Leeds, Adams began working for the Boots Company in Nottingham, England, founded by chemist Jesse Boots in 1921. Inspired by Wilhelmi’s elegant and pragmatic model, Adams spent the next 3 years perfecting his version of the UV erythema model using shaved guinea pigs. Up to that point, he was working as a lone biologist with a couple of assistants. By 1956 he had gathered enough information to request chemical support, and management assigned John Nicholson to him. The duo would have a 20-year-long collaboration that brought many drugs and much fortune to Boots, transforming a small drug firm into an internationally renowned powerhouse in the field of anti-inflammatory drugs. At first they identified phenoxylalkanoic acids, originally made as selective herbicides in the Agricultural Division. Among 600 phenoxylalkanoic acids, Adams, using his own model, found that BTS8402 was 10 times more potent than aspirin. Unfortunately, it was less potent as an analgesic when tested using the technique in which pressure was applied to a rat foot with edema. In 1960, Nicholson synthesized tert-butylphenyl-acetic acid, which was proven to be effective in rheumatoid arthritis. Sadly, it caused rash in some patients and had to be abandoned. A very similar drug, isobutylphenylacetic acid (ibufenac) did not cause a rash but did cause liver toxicity in a small number of patients after long-term use. Ibufenac was withdrawn in the United Kingdom but was in use in Japan for quite some time because it did not cause liver damage in the Japanese, a striking example of ethnic differences in adverse drug reactions. In the 1960s, Boots sent more than 38 tons of ibufenac to Japan. Finally, isobutylphenylpropionic acid (ibuprofen) was found to possess the best safety profile, although it was not the most potent. Boots marketed ibuprofen in the United Kingdom in 1969 with the trade name Brufen, and Upjohn marketed it in the United States in 1974 with the trade name Motrin. The active ingredient of Wyeth’s Advil and Bristol-Myers Squibb’s Nuprin is also ibuprofen. It is still widely used today and is regarded as the gold standard for over-the-counter analgesics. More impressively, millions of patients have taken ibuprofen in doses up to 1,600 milligrams without negative gastric effect. It has certainly lived up to its aspiration to be a super-aspirin.
The strikingly different safety profiles for ibufenac and ibuprofen may serve as a salient example of how much impact can be made on pharmacological effects by a small perturbation to a molecule. Ibuprofen (isobutylphenylpropionic acid) has only one carbon more than ibufenac (isobutylphenylacetic acid). Simply adding a methyl group to ibufenac provides ibuprofen, which is devoid of hepatotoxicity.
In the same class, naproxen is also a propionic acid with a similar pharmacology to that of ibuprofen. But naproxen is twice as potent as ibuprofen and has a much longer half-life in the body, enabling a once-daily regimen. Naproxen was discovered under the leadership of John Fried, who moved from Merck to Syntex to lead their medicinal chemistry program and eventually rose to be the president of the Syntex research division. Naproxen, introduced in 1976, is sold in the United States under the trade names Naprosyn and Aleve. At the height of naproxen’s popularity, its annual sales exceeded $1 billion, and Syntex became the only pharmaceutical company that flourished in the second half of the twentieth century until it was ultimately acquired by Hoffmann-La Roche in the late 1990s for over $6 billion. The patent for naproxen expired in December 1993, and the FDA approved naproxen sodium as an over-the-counter drug in 1994. Many newer drugs, such as the COX-2 selective inhibitors, have been tested against naproxen, whose fate is closely associated with them as well.
In all, about 30 NSAIDs have entered the market during the past 40 years, but none of them are devoid of gastrotoxic effects. In the United States alone, between 10,000 and 20,000 deaths are caused by NSAID-associated toxicity, such as perforations and bleeding of the stomach. An NSAID that is devoid of the gastrotoxic effect is still desired.
