Antiulcer agents cimetidine

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. 

On occasions, the useful biological activity may only be a minor property or a side-effect of a compound. The aim then would be to enhance the side-effect and eliminate the major biological activity. The story of the antiulcer agent cimetidine (Fig. 7.29) is a case in point. The desired biological property was selective antagonism of histamine receptors in the stomach. The lead compound was a histamine agonist with a very weak antagonism for the receptors of interest. 

This type of behaviour is not confined to polymorphs but may extend to pseudopolymorphic forms such as hydrates and solvates. A recent case of solvent-mediated phase transformation involved polymorphic and pseudopolymorphic forms of thiazole carboxylic acid [55], where the transformation is again sensitive to the composition of the mixed solvent. Three forms of the compound are known, an anhydrous form, a 0.5 hydrate, and a 1.5 hydrate. In 50-80% solutions (% = vol.% MeOH-H20), transformation of the 1.5 hydrate to the 0.5 hydrate was observed while transformation to the anhydrous form occurred in 85-100% solutions. No transformation occurred in 0-30% solutions. Detailed study of a solvent-mediated polymorphic transition has also been carried out for the antiulcerative agent cimetidine [56] for which seven polymorphic forms are known. An important feature of this study was the systematic use of seed crystals to induce crystallization at different supersaturation ratios. 

As discussed earlier, receptors are responsible for histamine induced gastric acid secretion. H -receptors antagonists such as cimetidine, ranitidine, famotidine etc. are used in the treatment of peptic ulcer and are discussed in chapter Antiulcer agents. ... 

The primary H2 blockers used to control gastric secretions are listed in Table 27-1. Cimetidine was the first H2 blocker to be widely used as an antiulcer agent. Newer drugs such as famotidine, nizatidine, and ranitidine appear to be at least as effective as cimetidine they differ from one another primarily in their phar-... 

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