Bioisosteric design of conformationally restricted pyridyltriazole histamine H2-receptor antagonists

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Abstract
A process of bioisosteric drug 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 in dogs so that the resulting agent, 3-amino-5-[2-(ethylamino)-4-pyridyl]-1,2,4-triazole (8) is more active than cimetidine.