Fifty years since the discovery of ibuprofen

K. D. Rainsford 0 0 K. D. Rainsford (&) Emeritus Professor, Biomedical Research Centre, Sheffield Hallam University , Howard Street, Sheffield S11WB, England, UK - Fig. 1 Professor Stewart Adams outside the BioCity Building in Nottingham which houses part of what were some of the original Boots Company Laboratories, now named in his honour, where development of ibuprofen was undertaken. Photograph kindly provided by Professor Adams and BioCity It is now 50 years since the discovery of the pharmacological effects of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen, and over 40 years since its introduction to clinical use as a prescription drug for the treatment of arthritic pain and inflammation (Adams 1987; Rainsford 1999, 2003). The initial discovery of the anti-inflammatory effects of ibuprofen in guinea pigs was made on 19 December 1961 by Dr. (now Professor) Stewart Adams, OBE (Fig. 1), the late Dr. John Nicholson (who was the chemist who synthesized the drug), and Mr. Colin Burrows at the Boots Co., Nottingham, UK (Rainsford 1999). The development of ibuprofen by the Boots Company, UK, was based on the need to have a safer form of aspirin (a Super Aspirin) without its gastro-intestinal effects, and also without the serious adverse effects of phenylbutazone and corticosteroids; these drugs being the principal antiinflammatory agents available at the time (Adams 1987; Rainsford 1999). This remarkable discovery was undertaken under what by present day standards that are rather basic laboratory conditions and without much knowledge of the mechanisms of inflammation and biochemical targets to use for drug actions. The discovery of ibuprofen was essentially made on an empirical basis. Indeed, there were many the twists and turns that took place during the discovery and development of ibuprofen from initial humble beginnings. It was only in the early 1970s that the actions of prostaglandins and their actions were established in mediating and regulating inflammation. It took longer still before assays for detecting anti-inflammatory activity based on prostaglandin synthesis inhibition were developed, as well as for the conditions for suitable assays understood, refined and validated for screening potential druggable agents. It is a great tribute to Dr. (now Professor) Stewart Adams and his colleagues that was through their insight and persistence which enabled the pharmacological activities of ibuprofen to be discovered and the clinical potential to be realized at a time when little was known about techniques for quantifying clinical responses in arthritic and other painful inflammatory conditions. Initially, after a long period of the synthesis of several hundred compounds Dr. Nicholson prepared, and Dr. Adams and Mr. Colin Burrows screened some 200 salicylate compounds as possible safer and more effective replacements for aspirin. Sadly, this proved unsuccessful although much important pharmacological information was gained from this work (Adams and Cobb 1967). Later, with the development and refinement of animal assays other compounds, including over 600 phenoxy-alkanoic acids (originally made as herbicides by Boots), were found to have more potent actions that aspirin or other salicylates in vivo (Nicholson 1982). As shown in the Table 1, there were several compounds that were found to have antiinflammatory activities which were introduced into clinical trials. Among these was the phenyl-acetic acid, RD 10499, and although this was active in rheumatoid arthritis (RA), it unfortunately produced rashes in about 20% patients, so leading to it being dropped from further clinical investigations. Later the phenyl-acetic acid, ibufenac, which did not produce rashes, was found to be effective in controlling pain and swelling in RA. Unfortunately, it caused severe liver reactions in patients in the UK but, curiously, not in Japan. The reason for this ethnic difference in liver toxicity does not seem to have been determined, but it is interesting, anecdotally, another phenyl-acetic acid NSAID, diclofenac, which also produces liver toxicity in Western patients, has not been observed to produce the same extent as those in Japan. The occurrence of liver toxicity led to efforts to establish if this was due to accumulation of the drug in the liver. Use of radiolabelled drugs, ibuprofen, it was found that this drug did not accumulate to the extent that was observed with ibufenac. With attention to the pharmacokinetics, gastro-intestinal and liver toxicity, ibuprofen was selected after an extensive programme of drug screening. It may not have been the most potent of the drugs evaluated but it had low toxicity. The recognition since that short half-life NSAIDs with little propensity to accumulate systemically has formed a basis for recognizing the safety of these drugs over those with longer half-lives or accumulation in key organs where untoward reactions may develop (Adams 1988). Indeed, subsequent evaluations have shown that the specific accumulation and persistence of some NSAIDs in their sites of action (i.e. effect compartment such as inflamed tissues) relative to their fast clearance from those organs (side-effect compartments, such as the blood, kidneys and liver) in which toxic reactions may occur with the NSAIDs may explain their relatively low propensity for adverse reactions from drugs like ibuprofen especially at low over-the-counter (OTC) doses (Brune 2007). These investigations have proven an important basis for what is known today about the relative safety of ibuprofen. The early clinical studies with ibuprofen in rheumatic patients were undertaken with cautious approach to dosage (Rainsford 1999). Safety data became available from some 19,000 patients and this was presented to the UK CSM in support of the case for non-prescription use of ibuprofen. Subsequently, the acceptance of its relative safety led to approval by the UK authorities in 1983 and in 1984 in the USA of low dose (\1,200 mg/day) for non-prescription Table 1 Summary of the history of the discovery of ibuprofen at the Boots co., and subsequent worldwide development 1953 Stewart Adams plans search for replacement for aspirin 1955 Development of guinea pig UV erythema as a potential screening assay for new compounds with anti-inflammatory activity 1956 Initiation of chemical development programme by the late Dr John Nicholson. Initially, screening of [200 salicylate compoundsproved no better than aspirin (Adams and Cobb 1967) 1960 Phenoxy-acid, RD 8402, in clinical trial. New strategy: search for analgesic and antipyretic with anti-inflammatory activity 1961 Phenyl acetic acid, RD 10355, active in clinical trials in RA, but rash in 5/12 patients led to it being abandoned. Anti-erythemic activity of ibuprofen discovered. UK Patent application February 1961; final specification September 30, 1964. 1962 Iso-butyl-phenyl acetate, Ibufenac, active clinically in RA, with no rash. In 1968, wit (...truncated)