title: Bioisosteric design of conformationally restricted pyridyltriazole histamine H2-receptor antagonists.
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.
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis*; D066298:In Vitro Techniques; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D006635:Histamine H2 Antagonists; D011725:Pyridines; D014230:Triazoles