Cimetidine structure

Progressive departure from the fundamental structure of the lead agent cimetidine led to the anti ulcer agent oxmetidine (47). The synthesis involves -methylation (CH3I) of the 2-thiouracil intermediate and is followed by an addition-elimination reaction with 2-(5-methyl-4-imidazolylmethylthio) ethylamine to give oxmetidine (47). ... 

The following amides prepared from 4-(3-nitro-l-pyrazolyl)butanoic acid, CDI, and primary amines represent partial structures of the histamine H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine [37]... 

Chlorination of the antacid cimetidine leads to the formation of four major DBFs cimetidine sulfoxide, 4-hydroxyhnethyl-5-methyl-7//-imidazole, 4-chloro-5-methyl-7//-imidazole, and a product proposed to be either a jS- or (5-sulfam. The formation of the last three products resulted from unexpected reactions and more substantial structural changes than those t3q)ically observed in chlorination [93]. 

Fig. 8.27 Structures of the thiourea-containing H2 antagonist metiamide, which caused blood dyscrasias in man, Cimetidine and its cyanoimino-containing analogue cimetidine which did not show similar adverse effects.

The main clinical use of H2 receptor antagonists is to inhibit gastric secretion in the treatment of stomach ulcers. These agents all contain features that relate to the histamine structure, in particular the heterocyclic ring. Cimetidine and ranitidine are the most widely used in this class. 

Traditional or Hj antihistamine drugs block many effects caused by histamine however, it turns out that they are not able to withstand events mediated by H2 receptors, in particular excess gastric juice secretion. In 1977 an H2-receptor antagonist, cimetidine, was proposed, which revolutionized stomach ulcer treatment. Later on, ranitidine was proposed, followed by drugs with minor structural and pharmacological differences such as famotidine and nizatidine. 

Cimetidine, the first released H2-blocker, like histamine, contains an imidazole ring structure. It is well absorbed following oral administration, with peak blood levels 45 to 90 minutes after drug ingestion. Blood levels remain within therapeutic concentrations for approximately 4 hours after a 300-mg dose. Following oral administration, 50 to 75% of the parent compound is excreted unchanged in the urine the rest appears primarily as the sulfoxide metabolite. 

Shibata, M., Kokubu, H., Morimoto, K., Morisaka, K., Ishida, T., and Inoue, M. (1983). X-ray structural studies and physicochemical properties of cimetidine polymorphi nRharm. Sci., 72 1436-1442. 

Attempts to quantitatively relate chemical structure to biological action were first initiated in the 19th century, but it was not until the 1960s that Hansch and Fujita devised a method that successfully incorporated quantitative measurements into SAR determinations (see section 4.4). The technique is referred to as QSAR (quantitative structure-activity relationships). One of its most successful uses has been in the development in the 1970s of the antiulcer agents cimetidine and ranitidine. Both SARs and QSARs are important parts of the foundations of medicinal chemistry. 

An interesting observation in our structure-activity studies was that ethylamine, a part of the histamine molecule, 4-(2-ethylamine)imidazole, known for a long time to be a potent stimulator of gastric secretion, also produced duodenal ulcers in rats (20,22). Furthermore, structural similarities also exist between dopamine and histamine H receptor antagonists metiamide and cimetidine (23,24). 

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. 

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