Development of cimetidine

One possible explanation for this is that the longer four-unit chain extends the 

Both the nitroguanidine and cyanoguanidine analogues of metiamide were synthesized and found to have comparable antagonist activities to metiamide. The 

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Subsequent to the development of cimetidine, H2 antagonism was discovered in compounds with rings other than imidazole. In particular, the drug ranitidine (35) was developed. It would appear that the di-... 

The following Case Studies show several examples of isosteres and bioisosteres in use. The story of the development of cimetidine also demonstrates the use of chain homologation. 

The assay used throughout the development of cimetidine was an animal assay on anesthetized rats. The rats were treated with histamine (11.36) to stimulate acid secretion. The same rats were then treated with a potential antagonist. Increases in stomach pH caused by administration of the antagonist were monitored to screen for activity. 

In the development of cimetidine (11.35), an extra methyl group was added to favor a desired tautomeric equilibrium as... 

The discovery and development of cimetidine and ranitidine provided a revolution in the medical treatment and management of peptic ulcer disease. Subsequently, many pharmaceutical companies became involved in research programs to discover additional compounds as H2-receptor histamine antagonists. As a result, a very wide range of chemical structures now exists for this class of drug (for a review, see Cooper et al. [19]). Many of these compounds have been investigated in human studies, but only the above-mentioned five drugs - cimetidine, ranitidine, nizatidine, famotidine, and roxatidine - are marketed as medicines. 

The development of cimetidine and captopril illustrate the new approach. Dozens of other drugs could have served as equally valid examples. These drugs are already well established in the market. Many of the agents under investigation now will only come to market after the turn of the century. The differences of opinion belie an underlying, widely shared philosophy ... 

Fig. 7.1-2 Development of cimetidine as a -selective agonist for the treatment of ulcers.

Histamine works by binding into a receptor in the stomach lining and stimulating the production of acid. What the developers of cimetidine at Smith, Kline and French wanted was a drug that would bind to these receptors without activating them and thereby prevent histamine from binding but not stimulate acid secretion itself. Unfortunately, the antihistamine drugs successfully used in the treatment of hay fever did not work—a different histamine receptor was involved. 

Cimetidine became available to the public in England in 1976 and in the United States in 1979, sold under the trade name Tagamet. Annual sales of this drug skyrocketed, ultimately reaching more than 1 billion in annual sales. Cimetidine earned its place in history as the first blockbuster drug. Since Ihe development of cimetidine, other H2 antagonists were developed and approved for use ... 

Brimblecombe RW, Duncan WAM, Durant GJ, et al. Characterization and development of cimetidine as a histamine Hz-receptor antagonist. Gastroenterology 1978 74 339. 

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