engleski

A rational approach to drug design-ranitidine example

A modern approach to a new drug development is based on rational drug design whereby drug is designed to interact with the corresponding receptor in a known biological system. The strenghts of the rational approach are amply demonstrated by the development of the first antiulcer drug cimetidine and the most important drugs from the same therapeutic group: ranitidine, famotidine and nizatidine. When the antiulcer programme started it was proposed that there might be two different types of histamine receptors-H1 receptors involved in the inflammation process and H2 receptor, but which would not activate it. The research started from histamine itself. The numerous modidfications of the histamine molecule where made. attaching of various alkyl and aryl substitents at different locations, increasing in hydrophobicity, prolongation of side-chain, introduction of groups such as guanyl, isothiourea, thiourea, cynoguanidine, replacement of imidazole ring with other heterocyclic system and introduction of electron donating or withby step, with minimal changes in the remaining parts of the molecule in order to follow their influences on conformation, ionization degree, pKa value, hydrophobicity, flexibility of the side-chain, orientation of dipole moment and pharmacological effect. From the beginning of the project until now several hundred compounds have been synthesized. The most important are: 4-methylhistamine (a highly selective H2 agonist), N-guanylhistamine (a partial agonist), burimamide (the first H2 receptor agonist), metiamide (a potent but too toxic antagonist), cimetidine (the first markated H2 receptor antagonist), and ranitidine (the worlds biggest selling prescription drug).

ranitidine; drug design; ulcer; histamine antagonist

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