Bioisosteric Design of Conformationally Restricted Pyridyltriazole Histamine H2-Receptor Antagonists

Article abstract of DOI:10.1021/jm00355a001

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.