Lipinski C A, LaMattina J L, Hohnke L A
J Med Chem. 1985 Nov;28(11):1628-36. doi: 10.1021/jm00149a015.
A process of drug design has previously been described that led to the synthesis of 3-amino-5-[2-(ethylamino)-4-pyridyl]-1,2,4-triazole (4), a competitive histamine H2-receptor antagonist structurally unrelated to, but more potent than, cimetidine. A QSAR study on a subset of analogues closely related to 4 showed that gastric acid antisecretory activity increased with decreasing lipophilicity. An SAR study about 4 focused on (1) pyridine substitution compatible with both unidentate and bidentate hydrogen bonding, (2) exploration of the pseudosymmetry of 4, and (3) examination of triazole and imidazole bioisosterism. This SAR study led to a definition of the minimum structural features required for antagonist activity. The pyridylamino group is not essential for activity since replacement with a methyl group results in a decrease but not loss of activity. The triazole amino group is also not essential since replacement of the triazole amino group by methyl results in very similar activity. A triazole ring nitrogen N-1 can be replaced by a CH as in imidazole 20. The same methylimidazole in 20 when appended to a methyl pyridine as in 22 produces a competitive antagonist with Schild plot slope of unity. In summary compound 22 displays the minimum features required for antagonist activity, namely a 4-substituted pyridine appended to a 4(5)-substituted imidazole ring with single nitrogen to amidine nitrogen pair distances of 5.16 and 6.42 A.
此前已描述了一种药物设计过程，该过程导致合成了3-氨基-5-[2-(乙氨基)-4-吡啶基]-1,2,4-三唑(4)，这是一种竞争性组胺H2受体拮抗剂，其结构与西咪替丁无关，但比西咪替丁更有效。对与4密切相关的类似物子集进行的定量构效关系研究表明，胃酸分泌抑制活性随亲脂性降低而增加。关于4的构效关系研究集中在：(1) 与单齿和双齿氢键均兼容的吡啶取代；(2) 对4的假对称性的探索；(3) 三唑和咪唑生物电子等排体的研究。该构效关系研究确定了拮抗剂活性所需的最小结构特征。吡啶氨基对于活性不是必需的，因为用甲基取代会导致活性降低但不会丧失。三唑氨基也不是必需的，因为用甲基取代三唑氨基会产生非常相似的活性。三唑环氮N-1可以如咪唑20那样被CH取代。20中的相同甲基咪唑连接到如22中的甲基吡啶上时会产生一种竞争性拮抗剂，其希尔德图斜率为1。总之，化合物22显示出拮抗剂活性所需的最小特征，即连接到4(5)-取代的咪唑环上的4-取代吡啶，单氮到脒氮的距离分别为5.16和6.42 Å。
