Christopher Lipinski - Bioisosteric design of conformationally restricted pyridyltriazole histamine H2-receptor antagonists.

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      Publication Details (including relevant citation   information): Lipinski, C. A., Journal of medicinal   chemistry, 1983, 26 (1), pp 1-6

      Abstract: A process of bioisosteric drug design   is described whereby, in a manner analogous to synthesis, key   portions of an effector molecule are successively replaced by   pharmacophores or bioisosteres. This process, when applied to   histamine, leads to the competitive histamine H2-receptor   antagonist prototype 3-amino-5-(2-amino-4-pyridyl)-1,2,4-triazole   (7). The biaryl nature of 7 fixes internitrogen distances, and   comparison of these with histamine suggests that 7 shares   structural features more in common with histamine trans rather   than histamine gauche conformations. Alkylation of the prototype   pyridylamino group in 7 markedly improves both histamine   H2-receptor antagonist and gastric acid antisecretory activity so   that the resulting agent,   3-amino-5-[2-(ethylamino)-4-pyridyl]-1,2,4-triazole (8), is more   active than cimetidine.

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