Tagamet Discovery of Histamine H2-receptor Antagonists - Landmark - American Chemical Society
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`» Discovery of Cimetidine
`
`Tagamet: The Discovery of Histamine H2 -receptor
`Antagonists
`International Historic Chemical Landmark
`
`Dedicated November 24, 1997, in Harlow, UK, and February 27, 1998, in King of Prussia, Pennsylvania, USA,
`at Smith Kline & French’s research facilities (now GlaxoSmithKline).
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`Commemorative Booklet (PDF)
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`It’s hard to believe that, just 20 years ago, a peptic ulcer could be a life-threatening condition. The discovery of
`the compound cimetidine (sold under the trademark Tagamet) by researchers at Smith Kline & French in 1970
`had a revolutionary impact on the treatment of this common disorder.
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`Contents
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`• Tagamet®: A Revolutionary Ulcer Treatment
`• New Era of Logical Drug Design
`• Discovery of Histamine H2-receptor Antagonists
`• Producing Tagamet®
`• The People Behind Tagamet®
`• Further Reading
`• Landmark Designation and Acknowledgments
`• Cite this Page
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`http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/cimetidinetagamet.html
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`5/9/2015
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`Tagamet Discovery of Histamine H2-receptor Antagonists - Landmark - American Chemical Society
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`“The discovery of histamine H2-receptor antagonists” commemorative booklet produced by the National Historic
`Chemical Landmarks program of the American Chemical Society in 1997.
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`Tagamet®: A Revolutionary Ulcer Treatment
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`As late as the 1970s, a peptic ulcer could be a life-threatening condition. Sufferers often endured periods of
`intense pain over many years, especially at mealtimes and at night, with social and economic repercussions for
`themselves and their families. Left untreated, an ulcer could result in severe bleeding and death.
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`http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/cimetidinetagamet.html
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`A major cause of ulcers is the release of excess stomach acid, which leads to breaches in the lining of the
`intestinal tract. Continuing acid secretion prevents healing. The main treatment used to be the administration of
`alkalis, which provided only temporary relief. Patients were told to rest and follow a bland diet. Surgery to
`remove part of the stomach was a last resort.
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`The discovery of the compound cimetidine by researchers at the UK laboratories of Smith Kline & French in the
`1970s, transformed the lives of millions of people. Sold under the trademark Tagamet®, it was the first effective
`anti-ulcer drug and had a revolutionary impact on treatment. Tagamet® profoundly decreases acid secretion,
`thus promoting healing and avoiding the need for surgery.
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`New Era of Logical Drug Design
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`The research program leading to cimetidine also represented a revolution in the way pharmaceuticals are
`developed. Traditionally, the development of a new drug would often depend on the fortuitous discovery of a
`plant or microbial extract that showed some of the required biological activity. Using that first extract as a lead,
`many similar compounds would be made and tested for pharmacological effectiveness. In many cases, the
`researchers did not know how the drug worked, so finding an optimal compound was difficult.
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`The development of cimetidine was radically different: It was one of the first drugs to be designed logically from
`first principles. Smith Kline & French's multidisciplinary research team first looked at the physiological cause of
`acid secretion. They confirmed that a molecule found in the body called histamine triggers the release of acid
`when it binds to a specific receptor (now called the H2-receptor) in the stomach lining. Their aim was to find a
`molecule that successfully competed with histamine in combining with the receptor, but then blocked, rather
`than stimulated, acid release. Such a molecule was called a histamine H2-receptor antagonist and represented
`a new class of drugs.
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`Using a step by step analysis of structural and physical properties, the team made a series of histamine-based
`molecules, which were then tested for antagonist activity using carefully designed pharmacological assays.
`Today, this approach of rational drug design underpins the discovery programs of many major pharmaceutical
`companies.
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`Discovery of Histamine H2-receptor Antagonists
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`The discovery of histamine H2-antagonists is a story of single-minded commitment by a group of creative
`scientists working in close collaboration in the United Kingdom. The process of research and development for
`economical production of the resulting drug, cimetidine, was the work of equally creative scientists working in
`the United States.
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`Discovery of H2-receptor Antagonists
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`In 1963 George Paget, a pathologist from ICI (Imperial Chemical Industries), joined Smith Kline & French to
`head its R&D laboratories at Welwyn Garden City in the United Kingdom. He soon recruited two colleagues:
`James Black as head of pharmacology and William Duncan as head of biochemistry.
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`Black had been instrumental in developing beta-blocker drugs for the treatment of heart disease. They were
`based on his notion of blocking the stimulating action of a molecule (agonist) at a receptor site implicated in the
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`http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/cimetidinetagamet.html
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`disease with a similar but inactive chemical (antagonist). He was keen to start a new research program looking
`at histamine receptors and antagonists.
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`Histamine is found throughout body tissues and is released during allergic reactions such as hay fever. It also
`stimulates acid secretion in the stomach and increases the heart rate. However, tests with antihistamines had
`indicated there were possibly two types of histamine (H) receptor, one of which did not respond to
`antihistamines. Black wanted to establish the existence of the latter receptor and to find histamine antagonists
`that selectively inhibited acid secretion. Since this work promised to lead to an effective anti-ulcer medicine, the
`company started an acid secretion program in 1964.
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`Chemists Graham Durant, Robin Ganellin, and John Emmett joined Black on the project together with Mike
`Parsons, a pharmacologist. Their aim was to make chemical variants of histamine and test them for antagonism
`using a combination of in vitro and in vivo assays.
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`A New Receptor
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`The histamine molecule has a ringlike structure with a short side chain attached. Black's first idea was to alter
`the ring by tacking on chemical groups. Although no antagonists were found, it did produce an agonist called
`4-methylhistamine, which stimulated acid secretion without any of the other histamine responses. This proved
`the existence of a second receptor, thus establishing a clear target for drug research. The project was then
`renamed the H2-receptor program.
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`However, finding and synthesizing potential histamine antagonists turned out to be more difficult than expected.
`By 1968, of the 200-odd compounds made, none had shown any activity in the assays. Fortunately, Parsons
`recognized that modifying the assays would increase their sensitivity. The team then retested a compound
`Durant had made earlier and found that it showed partial antagonism.
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`Tagamet®: A Revolutionary Treatment
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`Durant's compound became the lead, and after two years of hard work, an active antagonist called burimamide
`was produced. Burimamide was not orally active and so a new analogue, metiamide, which was orally active
`and ten times more potent, replaced it. The results of clinical trials with metiamide begun in 1973 were
`impressive: ulcers were healed within three weeks. Unfortunately, metiamide gave rise to a blood disorder
`called agranulocytosis as a side effect of treatment. This had been anticipated as a possibility, so as an
`insurance policy, the team prepared a similar compound replacing the thiourea group with a cyanoguanidine
`moiety.
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`The new lead compound, cimetidine, passed every test with flying colors and in November 1976 was launched
`as Tagamet® (derived from the anTAGonist and ciMETidine). Tagamet® was greeted with great enthusiasm by
`doctors and patients alike. Ten years after its introduction, it had achieved sales of one billion dollars and had
`become the world's number one prescription drug.
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`Producing Tagamet®
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`With the spectacular success of Tagamet®, it became very important to discover an economic process to make
`cimetidine. The production volume was expected to reach 1,000 tons a year - a large amount by
`pharmaceutical standards.
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`Process Patent Protection for Tagamet®
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`The initial process used to prepare cimetidine, while adequate for initial supplies, involved a bottleneck step
`which required the reduction of an imidazole ester intermediate using lithium aluminum hydride (LAH). The LAH
`process was difficult and expensive to operate and was threatened by a shortage of LAH supplies. Because of
`the high dose of cimetidine, cost reductions were essential to make the revolutionary new drug successful in
`the market. Since cimetidine was anticipated to be a worldwide success, it also would require patent protection
`around the world, including countries that offered process patent protection only.
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`To address these issues, Charles Berkoff and Elvin Anderson established a process research effort at the
`Smith Kline & French research and development facilities in Philadelphia aimed at finding cost-effective,
`practical, and patentable routes for synthesizing cimetidine. Groups headed by George Wellman and Lee Webb
`were among the first in the industry to emphasize the search for new synthetic methods instead of optimization
`of existing processes.
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`The initial objective was to find alternative routes to an alcohol intermediate. A number of alternate methods of
`preparing the alcohol were devised and patented, and the most cost-effective method, using sodium in liquid
`ammonia for the reduction of the ester, was finally implemented. This cleaner, less expensive pathway helped
`cut tens of millions of dollars per year from the manufacturing cost. Many of the other innovative methods of
`preparing cimetidine also provided process patent protection and therefore enhanced exclusivity in countries
`around the globe. This process patent strategy was especially important in Japan, where it was not possible to
`protect the product any other way.
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`A Better Manufacturing Process
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`Manufacturing of cimetidine was begun at Cork, Ireland, where production increased from approximately 18
`metric tons in 1976 to about 1,000 metric tons by 1982. This dramatic increase in production demand led to
`further streamlining and perfection of the process. Low-cost cysteamine equivalents were implemented, and the
`alcohol was eventually acquired from a company that had developed a new manufacturing method employing a
`hydroxymethylation reaction. The number of operational steps was reduced and the throughput was
`dramatically improved so that the hundreds of tons of drug substance could be manufactured economically and
`in an environmentally friendly manner.
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`Just as the discovery of cimetidine is a landmark in logical drug design, so the discovery and development of
`efficient synthetic routes to cimetidine is a landmark in process research and development.
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`Inside the SmithKline Beecham (now GlaxoSmithKlein) chemical manufacturing facility in County Cork, Ireland,
`where cimetidine, the active ingredient in Tagamet, is made.
`Courtesy SmithKlein Beecham Pharmaceuticals.
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`Discovery and Development Team behind Tagamet®
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`United Kingdom Discovery Research
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`Sir James Black was born in Scotland in 1924. He studied medicine at the University of St Andrews. His work
`at Smith Kline & French on establishing the role of the histamine H2-receptor in acid secretion leading to the
`discovery of antagonists must be considered his most significant achievement. It followed on naturally from his
`pioneering research carried out at ICI on beta-adrenogenic antagonists, or beta-blockers. On leaving Smith
`Kline & French in 1973, he took up the chair of Pharmacology at University College London. Four years later,
`he moved to Wellcome as Director of Therapeutic Research. In 1984 he was named Professor of Analytical
`Pharmacology at Kings College London. He was awarded the Nobel Prize for Medicine in 1988.
`
`C. Robin Ganellin, born in London 1934, read chemistry and took his Ph.D. at Queen Mary College London.
`Following postdoctoral research at MIT, he joined Smith Kline & French in 1960 as a medicinal chemist and
`eventually became Vice President of Research at Welwyn. In 1986 he was appointed to the Smith Kline &
`French chair of Medicinal Chemistry at University College London. He received numerous awards from learned
`societies for his work on histamine H2 antagonists.
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`Graham J. Durant was born in 1934 in Wales and obtained his first degree and Ph.D. in chemistry from the
`University of Birmingham. Following postdoctoral work at the State University of Iowa, he joined Smith Kline &
`French in 1959. At the time he had a particular interest in guanidine chemistry which proved to be invaluable in
`the development of cimetidine. He became Head of Medicinal Chemistry before moving to establish the Center
`for Drug Design and Development at the University of Toledo in 1987 where he became Distinguished
`Professor of Medicinal Chemistry. In 1992, he became Senior Director of Chemistry at Cambridge
`Neurosciences in Cambridge, Massachusetts.
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`William Duncan who was Director of Research gave his unwavering support through all the low periods and
`when closure of the research program seemed likely.
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`John C. Emmett joined Smith Kline & French in 1965 and immediately became part of the team working on the
`H2 antagonist problem. Following the successful work leading to cimetidine, he moved into the area of selective
`thyromimetics and later became Head of Medicinal Chemistry.
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`Michael Parsons provided the essential pharmacological support characterizing the new receptor and the
`antagonist activity of the compounds made.
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`United States Development Research
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`R. Lee Webb was born in Australia in 1944. He obtained his bachelor’s degree with honors from the University
`of Melbourne and a Ph.D. in organic chemistry from the Pennsylvania State University in 1969. After two years
`of post-doctoral work at Indiana University he joined Smith Kline & French Laboratories as a medicinal chemist
`in 1971. Following work on the anthelmintics oxibendazole and albendazole (Zentel) he teamed up with George
`Wellman to form the Process Chemistry group in 1975 for the work on Tagamet®.
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`George Wellman was born in Detroit in 1945. He entered Kalamazoo College in 1963 and received a B.A. in
`1967. Staying in chemistry and in Kalamazoo, he continued his studies at Western Michigan University where
`he received a M.A. degree in 1969 and a Ph.D. in 1972. He was awarded an NIH postdoctoral fellowship and
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`http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/cimetidinetagamet.html
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`continued his postdoctoral research at the University of Michigan. He joined Smith Kline & French Laboratories
`in 1973 working in process chemistry at the Spring Garden laboratories in Philadelphia.
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`Charles E. Berkoff and Elvin L. Anderson initiated the work to identify more efficient manufacturing
`processes. Bing Lam, Wilford Mendelson, Joseph Lewis, and Cliff Labaw worked with Wellman and Webb and
`were key contributors to the search for efficient processes for manufacturing cimetidine.
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`Further Reading
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`• The discovery of histamine H2-receptor antagonists (Royal Society of Chemistry)
`• Our History: 1976 (GlaxoSmithKline)
`• James White Black (Chemical Heritage Foundation)
`• Autobiography of Sir James W. Black (Nobelprize.org)
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`Back to top
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`Landmark Designation and Acknowledgments
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`Landmark Designation
`
`The American Chemical Society and the Royal Society of Chemistry dedicated the discovery of histamine
`H2-receptor antagonists, which led to the development of Tagamet®, as an International Historic Chemical
`Landmark on November 24, 1997, in Harlow, UK, and on February 27, 1998, in King of Prussia, Pennsylvania,
`U.S.A, at SmithKline Beecham’s research facilities (now GlaxoSmithKline). The plaques commemorating the
`events read:
`
`Pioneering work by scientists in the laboratories of this company led to the first clinically effective inhibitor
`of gastric acid secretion. The worldwide introduction of cimetidine (Tagamet) revolutionized the treatment
`of peptic ulcers by dramatically reducing the need for surgical intervention. The work is recognized as the
`classic example of the systematic modification of a natural messenger substance (histamine) to create a
`therapeutically useful blocking agent. Effective commercialization of this discovery was greatly facilitated
`by the subsequent investigation and design of novel synthetic routes, which led to the development of an
`efficient chemical manufacturing process.
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`Acknowledgments
`
`Adapted for the internet from “The discovery of histamine H2-receptor antagonists,” produced by SmithKline
`Beecham Pharmaceuticals, the Public Affairs Department of The Royal Society of Chemistry and the Office of
`Public Outreach of the American Chemical Society in 1998.
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`Back to top
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`Cite this Page
`
`American Chemical Society National Historic Chemical Landmarks. Tagamet®: Discovery of Histamine H2-
`receptor
`Antagonists. http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/cimetidinetagamet.html
`(accessed Month Day, Year).
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`Back to Landmarks Main Page
`
`Learn more: About the Landmarks Program
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`Take action: Nominate a Landmark and Contact the NHCL Coordinator
`
`Chemists Robin Ganellin, John Emmett, and Graham Durant (left to right), met regularly to discuss the next
`chemical step in their search for an effective drug (undated).
`Courtesy SmithKlein Beecham Pharmaceuticals.
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`Lee Webb (left) with Bill Edgerton of Smith Klein & French Corporate Patents in 1975.
`Courtesy SmithKlein Beecham Pharmaceuticals.
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`George Wellman, (third from left) and staff conducting a sodium in liquid ammonia reduction at Upper Marion,
`King of Prussia, Pa., in 1975.
`Courtesy SmithKlein Beecham Pharmaceuticals.
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