Lipinski C A
J Med Chem. 1983 Jan;26(1):1-6. 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.
描述了一种生物电子等排体药物设计过程，在此过程中，以类似于合成的方式，效应分子的关键部分被药效基团或生物电子等排体依次取代。该过程应用于组胺时，可得到竞争性组胺H2受体拮抗剂原型3-氨基-5-(2-氨基-4-吡啶基)-1,2,4-三唑(7)。7的联芳基性质固定了氮原子间的距离，将这些距离与组胺的进行比较表明，7与组胺反式构象而非组胺gauche构象具有更多共同的结构特征。7中原型吡啶氨基的烷基化显著提高了组胺H2受体拮抗剂活性和胃酸分泌抑制活性，使得所得药物3-氨基-5-[2-(乙氨基)-4-吡啶基]-1,2,4-三唑(8)比西咪替丁更具活性。
