Tagamet

The development of tagamet revolutionized the treatment of duodenal and gastric (stomach) ulcers and other disorders, such as heartburn associated with acid reflux, that require a reduction in the amount of gastric acid secreted in the stomach. Before the introduction of the drug, treatment of peptic ulcers--the collective name for gastric and duodenal ulcers--relied on extensive bed rest, imposition of a bland diet, treatment with antacids and/or anticholinergics, and often involved surgery if the ulcer recurred.

Tagamet was the first clinically effective histamine H₂-receptor antagonist. Histamine is an agonist found throughout body tissue that plays a key role in the regulation of various physiological processes. It acts at special sites in the body known as histamine receptors, of which there are four subtypes: H₁, H₂, H₃, and H₄. In the stomach, histamine stimulates gastric acid production by interacting with the H₂-receptors of the parietal cells. H₂-receptor antagonists reduce the volume and acidity of gastric fluids by blocking the H₂-receptors.

The project that led to the discovery of H₂-receptor antagonists and cimetidine was initiated by Sir James W. Black when he joined SmithKline & French at Welwyn Garden City, England, in 1964. Black, now emeritus professor of analytical pharmacology at King's College, London, received the Nobel Prize for Physiology or Medicine in 1988 for the development of beta-blockers--used for the treatment of coronary heart disease, high blood pressure, and heart failure--and the discovery of H₂-receptor-blocking drugs.

Between 1964 and 1968, Black's team synthesized around 200 compounds chemically related to histamine and tested them for histamine antagonism.

"Our aim was to find histamine analogs that bound to H₂-receptors but were sufficiently different from histamine not to stimulate gastric acid secretion," explains team member C. Robin Ganellin, who is now emeritus professor of medicinal chemistry at University College London. Other team members included Graham J. Durant, John C. Emmett, William A. M. Duncan, and Michael E. Parsons, who is now professor of pharmacology at the University of Hertfordshire, Hatfield, England.

None of the 200 or so compounds showed any blocking activity in the assays except for a histamine analog with an alkyl side chain terminating with a guanidine group [NHC(NH)NH₂]. "We subsequently found that analogs with longer chains were more effective at blocking," Ganellin says.

THE COMPOUNDS had mixed activities, acting as both agonists and antagonists. The researchers therefore decided to replace the strongly basic guanidine group with nonbasic groups. They focused on groups that are essentially neutral in water. Eventually, they discovered a thiourea derivative that exhibited weak activity as an antagonist but did not act as an agonist. Lengthening the side chain of this derivative and syntheses of substituted analogs led to the discovery of burimamide, a pure antagonist without agonist effects [Nature 1972, 236, 385].

Burimamide proved not to be sufficiently active for oral use. "We knew it was not very potent and would have to be given by injection," Ganellin notes. A related compound, metiamide, was found to be 10 times more potent, but clinical trials revealed that the compound led to a reduction of the number of white blood cells in some patients. The most likely cause of this toxicity was thought to be the thiourea group.

Three of the researchers--Durant, Emmett, and Ganellin--turned their attention to nonthiourea analogs of metiamide, including a cyanoguanidine compound called cimetidine. The compound was synthesized in 1972 and evaluated for toxicology by 1973. It passed all trials.

The drug was first marketed by SmithKline & French in the U.K. in November 1976, and in the U.S. in August 1977. By 1979, Tagamet was being sold in more than 100 countries and became the top-selling prescription product in the U.S., Canada, and several other countries.

In November 1997, the American Chemical Society and the Royal Society of Chemistry in the U.K. jointly recognized the work as a milestone in drug discovery by designating it an International Historic Chemical Landmark during a ceremony at SmithKline Beecham's New Frontiers Science Park research facilities in Harlow, England.

Tagamet is now manufactured by GlaxoSmithKline (GSK), which was formed by the merger of Glaxo Wellcome and SmithKline Beecham in 2000. The company also markets ranitidine (tradename Zantac), an H₂-receptor antagonist and analog of cimetidine developed by Glaxo.

Since the advent of H₂-receptor antagonists, a new generation of drugs, known as proton pump inhibitors, has emerged for the treatment of peptic ulcers. They work by inhibiting H⁺/K⁺-ATPase, the hydrogen-potassium adenosine triphosphatase enzyme that is involved in pumping gastric acid into the stomach.

"Tagamet has now been largely replaced by the proton pump inhibitors for treating peptic ulcers," a GSK spokesperson remarks. "Tagamet is now available as an over-the-counter medicine for heartburn in many countries, this method of purchasing the brand resulting in almost as much sales as those by prescription."

Cimetidine

Name: N-Cyano-N''-methyl-N"'-{2-{[(5-methyl-1H-imidazol-4-yl) methyl]thio} ethyl}guanidine

CAS Registry: 5U81-61-9

Other names: Tagamet

Introduced: 1976, SmithKline & French

Did you know that the name Tagamet is derived from the words "anTAGonist" and "ciMETidine?"