Chapter 18 Development and Application of Cimetidine
Stomach ulcer had been a fatal disease until late 1970s. The patients were often at times of intense pain for many years, especially at night and in the mealtime. Without treatment, the ulcer can lead to bleeding and death. The primary cause of the ulcer is the release of stomach acid, which causes severe damage in the lining of the intestinal tract. Continuous secretion of the acid prevents healing. A temporary treatment required the administration of alkalis for only a short relief of the symptom. Partial removal of the stomach by surgery was the final solution.
The discovery of cimetidine by researchers at the laboratories of Smith Kline and French (SK&F) (now Glaxo Smith Kline) in UK in the 1970s saved the lives of millions of patients. It was the first effective drug to combat the ulcer and had a revolutionary impact on the treatment by significantly decreasing the acid secretion, and therefore, avoided the need for surgery.
Rational Drug Design
The ulcer project at SK&F was also a revolution in the ways drugs are developed. Creation of new drugs usually involved accidental discovery of a plant or microbial extract which demonstrates some of the desired biological activity. With the first extract as the lead, many of the similar compounds are tested for pharmacological efficacy. In many cases, researchers do not know how the drug works, thus it is difficult to find a better drug candidate.
Fundamentally different from traditional approach, cimetidine was developed from first principles. SK&F’s multi-disciplinary research team first studied the physiological causes of the acid secretion. They confirmed that a molecule in the body called histamine triggers the release of acid when it goes to a specific protein (now known as the H2-receptor) in the gastric mucosa. The researchers’ aim was to develop molecules that can successfully compete with histamine in binding with the receptor, and inhibit, but not promote, the acid release. These molecules are called histamine H2-receptor antagonists and form a new class of the anti-ulcer drugs.
During the analysis of the structure and properties, the research group synthesized a series of histamine molecules, which were tested for antagonist activity by careful pharmacological design. Nowadays, this kind of strategy for the rational development is the basis of the drug discovery projects in many large pharmaceutical companies.
Novel H2-Receptor Antagonists
In 1963, George Paget, a pathologist from ICI, joined SK&F and headed its R&D laboratories in Welwyn Garden City in UK. He quickly recruited two colleagues: James Black and William Duncan as Head of the Pharmacology and Head of Biochemistry, respectively.
Black played a pivotal role in the development of P-blocker drugs to treat cardiovascular diseases. They were based on his notion of inhibiting the stimulating effect of a molecule (agonist) on the receptor in the related disease with a similar, but inactive compound (antagonist). He wanted a new research program investigating histamine receptors and antagonists.
Histamine in body tissues is released in allergic reactions such as hay fever. It also promotes the secretion of the stomach acid and increases the heart rate. However, tests with antihistamines (a group of medications that block or interfere the effects of histamine) have indicated there might exist two possible types of histamine (H)-receptor, one of which did not respond to the antihistamines. Black initiated to establish the existence of the latter histamine receptor and find antagonists that could selectively block the acid secretion. Since this study seemed to lead to an effective anti-ulcer medicine, the company initiated an acid secretion program in 1964.
Graham J. Durant, Robin Ganellin, and John Emmett, who were all Ph.D. chemists, joined Black on the project, along with Mike Parsons, a pharmacologist. Their goal was to synthesize chemical derivatives of histamine and examine their antagonism with a combination of in vitro and in vivo tests.
The histamine molecule contains an imidazole ring structure with a short side chain. Black’s first idea was to make derivatives on the ring with different chemical groups. Despite the fact that no antagonists were found, they found an agonist 4-methyl histamine, which stimulates the secretion of the acid, without other histamine responses. This proved the existence of a second receptor as a new target for drug candidates. The project was renamed the H2-receptor program.
Optimization and Screening of the Drug Candidates
In the attempts to discover drugs acting as antagonists of histamine at H2 receptors Ganellin et al. have tried to use chemical properties to provide a link between chemical structure and the biological properties and have drawn heavily upon physical organic chemistry. This led naturally into the dual exercise of determining the chemical properties of drug molecules and of trying to discern which properties were most critical for biological activity. There is a continuous process, viz., one is continuously analyzing for relationships between chemical properties and biological activity, then predicting the next compounds to be made, and, finally, finding out how to synthesize them.
Ganellin et al. thought of an antagonist having some chemical similarity to histamine to aid receptor recognition, being sufficiently different so as not to stimulate a response, and possessing additional groups to assist receptor binding. The team spent four years and made some 200 compounds before uncovering a lead, viz., Nα-guanylhistamine, which was very weakly active as an inhibitor of histamine stimulation; it had indeed been synthesized at the beginning of the research by Dr. Graham Durant but it had been missed in the initial testing because it also acted as a stimulant. It was in fact later shown to be a partial agonist. Within a few days, another early compound synthesized by Dr. John Emmett was found to be more active, viz., the analogous isothiourea. These compounds were the first real leads, and the task was to synthesize a much more potent antagonist. The structures are obviously closely related, being simple isosteric N and S analogues.
Structural variables initially identified for study were the amidine groups, amidino N-substituents, side-chain length, and alternatives to imidazole. The amidine group differs from the ammonium group in histamine in being planar and in having more opportunities for H bonding. Ganellin et al. envisaged that it might act as an antagonist through H bonding with carboxylate side chains of proteins.
The apparent non-additivity between structural change and biological effect posed a typical problem familiar to all practicing medicinal chemists; viz., with so many structural variables to study (e.g., ring, side-chain length, amidine system, amidine substituents), there are many hundreds of structures incorporating different combinations of these variables, and one cannot make and test them all. What then should govern the selection? Ganellin believed that an essential feature of the discipline in medicinal chemistry is to find logical bases for defining the boundary conditions for the selection of structures for synthesis. In this case, Ganellin et al. continuously searched for useful physicochemical models for studying the chemistry of these compounds and used the inconsistencies in the structure-activity pattern to challenge the model or to reexamine the meaning of the biological test results. This dialogue, a search for self-consistency between the chemistry and the biology, is vital to new drug research where no precedent exists.
However, they were not making major progress. The problem seemed to be that the compounds of amidines subtituents had mixed activities, although to varying degrees. They mainly acted both as agonists and as antagonists; i.e., they appeared to be partial agonists. This meant that the compounds could block histamine, but they could not block acid secretion, since they acted as stimulants. In an attempt to separate these activities, the strongly basic amidine group was replaced by nonbasic groups which, though polar, would not be charged. Some nonbasic analogues were made, and these were found to lack stimulant activity but, unfortunately, they were not antagonists!
Eventually an TV-methyl thiourea analogue with its side chain lengthened, burimamide, was found to be a pure competitive antagonist without agonist effects. Burimamide was shown to be an effective inhibitor of histamine-stimulated gastric acid secretion in the rat, cat, dog, and human. It was also shown to be a highly specific and competitive antagonist of histamine on two in vitro non-H1test systems, viz., histamine stimulation of the rate of the spontaneously beating guinea pig right atrium and histamine inhibition of electrically evoked contractions of the rat uterus, thereby defining histamine H2 receptors and allowing burimamide to be classified as an H2-receptor histamine antagonist.
Further substitution to be made was the replacement of a methylene group (-CH2-) by the isosteric thioether linkage (- S -) at the carbon atom next but one to the ring, to afford “thiaburimamide” which was found to be more active as an antagonist. It was also argued that incorporating an electron-releasing substituent in the vacant 5 position of the ring, such as a methyl group, should not interfere with receptor interaction, since 4-methylhistamine having been shown to be an effective H2-receptor agonist. This approach was successful, and introduction of a methyl group into the ring of the antagonist furnished the more potent drug metiamide. The two ring substituents appeared to have electronic effects of equal magnitude but of opposing effect on ring p Ka.
Although the above molecular manipulations were made through consideration of the electronic effects of substituents and the first compounds prepared were those most accessible synthetically, evidence has subsequently accrued to suggest that conformational effects are probably more important. Crystal structure studies indicate that the thioether linkage may increase molecular flexibility and the ring-methyl group may assist in orientating the imidazole ring. Furthermore, the oxygen (ether) analogue which should fulfill the electronic requirements is less potent than burimamide, possibly by encouraging a different conformation through intramolecular H bonding. Metiamide is not only orally active but ten times more effective than burimamide in vitro. Clinical trials with metiamide began in 1973 and produced impressive results: ulcers were healed within three weeks. However, out of 700 patients treated there were a few cases of granulocytopenia, which, although reversible, limited the amount of clinical work.
The possibility existed that the granulocytopenia associated with metiamide was caused by the thiourea group in the molecule and this led to the need to examine more compounds. Fortunately, the team had sought alternatives to the thiourea group. One approach taken was to examine isosteric replacement of the thiourea sulfur atom ( = S) of metiamide. Replacement by carbonyl oxygen ( = O) gave the urea analogue, but this was much less active. Ganellin et al. returned to the idea of guanidine derivatives which had provided the original breakthrough. Replacement by imino nitrogen (=NH)afforded the guanidine which, interestingly, was not a partial agonist but a fairly active antagonist. However, in vitro, the urea and guanidine isosteres were both about 20 times less potent than metiamide, and other ways were investigated for removing the positive charge. It came to their attention that nitroguanidine was not basic, and further investigation revealed a publication by Charton on the Hammett relationship between σ and p Ka, for substituted amidines and guanidines. Guanidine basicity is markedly reduced by electron-withdrawing substituents, and Charton demonstrated a high correlation between the inductive substituent constant σ1and p Ka, for a series of monosubstituted guanidines. The cyano and nitro groups are sufficiently electron withdrawing to reduce the p Ka, by over 14 units, to values < 0; indeed, the ionization constants of cyanoguanidine (p Ka=-0.4) and nitroguanidine (p Ka=-0.9) approach that of thiourea (p Ka=-1.2). The nitroguanidine and cyanoguanidine analogues of metiamide synthesized by Durant et al. were found to be active antagonists comparable with metiamide. Of these two compounds, the cyanoguanidine is slightly more potent and was selected for development.
The new compound, cimetidine, passed all the animal and clinical tests, and in November 1976, was introduced in the market as Tagamets (coined from the antagonists and cime/idine). Doctors and patients greeted Tagamets with great enthusiasm. Ten years after it was introduced, it had a sales volume of over one billion dollars, and had become the world’s number one prescription drug.
Improving Manufacturing Process
The finding of the histamine H2 antagonist cimetidine is a story of dedication by the creative team working in seamless co-operation in UK. The research and development for the cost reduction of the production process was the work of innovative scientists in the US. After the spectacular success of Tagamets, it became very important to improve the process of the cimetidine economically. The expected production volume would reach 1000 tons per year-a large quantity by pharmaceutical standards.
First, in the process for the preparation of cimetidine, while sufficient for making the initial supplies, the reduction of an imidazole ester intermediate with lithium aluminum hydride (Li Al H4) became a bottleneck step. It was difficult and expensive to operate the Li Al H4 process, which was also threatened by a shortage of the Li Al H4 supply. Because of the high dose of cimetidine, a cost reduction in the process was necessary for the revolutionary new drug to be successful in the market. In addition, it would require patent protection worldwide, including in countries where only process patents are offered.
To tackle these problems, Charles Berkoff, Alvin Anderson, and several coworkers began to research the process at Smith Kline and French’s R&D facilities in Philadelphia, in search of cheap, practical, and patentable routes for synthesis of cimetidine. They emphasized the exploration of new synthetic methods rather than optimizing existing processes.
The original objective was to provide alternatives to an alcoholic intermediate. A number of alternative methods for generating the alcoholic intermediate had been developed and patented, and the most cost effective way, with sodium in liquid ammonia to reduce the ester, had been established. Tens of millions of dollars per year was saved from the cost of production by going through this cleaner, less expensive pathway. Many of the other innovative methods of cimetidine also provided process patent protection and thus the extension of exclusivity in countries around the world. This kind of process patent was quite important in Japan, where it was not possible to protect the product in any other way.
New production of cimetidine was started in Cork, Ireland, where the manufacturing capacity was increased from around 18 tons in 1976 to around 1000 tons in 1982. This increase has led to further streamlining and improvement of the procedures. The alcoholic intermediate was eventually obtained by a new manufacturing method employing a hydroxymethylation reaction, and equivalents for low-cost cysteamine were implemented. The total number of operational steps was reduced and the throughput was dramatically improved so that hundreds of tons of the drug could be manufactured both economically and in an environmentally friendly manner.
James Black should be recognized for introducing the role of histamine H2-receptor in acid secretion that leads to the discovery of antagonists. He was awarded the Nobel Prize for Medicine in 1988.