Lipinski C A, LaMattina J L, Oates P J
J Med Chem. 1986 Nov;29(11):2154-63. doi: 10.1021/jm00161a005.
The structural relationship of the competitive histamine H2-receptor antagonist 3-amino-5-(2-amino-4-pyridyl)-1,2,4-triazole (1) to the agonist histamine and to antagonists of the cimetidine type was explored by the design and synthesis of four series of bioisosterically designed prototypes. Biological data from these series was best interpreted as indicating a similarity between the imidazole moiety of histamine and cimetidine and the 2-amino-4-pyridyl moiety of 1. On the basis of this data, sequential replacement of 2-amino-4-pyridyl by 2-[(dimethylamino)methyl]-5-furyl and 2-guanidino-4-triazolyl moieties led to a structurally more potent series of biaryl histamine H2-receptor antagonists. The best of these, 2-methyl-4-(2-guanidino-4-thiazolyl)imidazole (29, CP-57,361-1) was 120 times more potent as a histamine H2-receptor antagonist than 1.
通过设计和合成四个系列的生物电子等排体设计原型，探究了竞争性组胺H2受体拮抗剂3-氨基-5-(2-氨基-4-吡啶基)-1,2,4-三唑(1)与激动剂组胺以及西咪替丁类型拮抗剂之间的结构关系。这些系列的生物学数据最能说明组胺和西咪替丁的咪唑部分与1的2-氨基-4-吡啶基部分之间存在相似性。基于这些数据，用2-[(二甲氨基)甲基]-5-呋喃基和2-胍基-4-三唑基部分依次取代2-氨基-4-吡啶基，得到了一系列结构上更有效的联芳基组胺H2受体拮抗剂。其中最好的化合物2-甲基-4-(2-胍基-4-噻唑基)咪唑(29，CP-57,361-1)作为组胺H2受体拮抗剂的效力比1强120倍。
