Conformational requirements for histamine H2-receptor inhibitors: a structure-activity study of phenylene analogs related to cimetidine and tiotidine

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Abstract
Two series of compounds related to cimetidine and tiotidine were synthesized as part of a study to evaluate the importance of conformational parameters in binding at histamine H2 receptors. The flexible methylthioethyl connecting chain was replaced by a conformationally restricting phenylene unit. These compounds [including N-cyano-N''-methyl-N''''-[4-[5(4)-methyl-4(5)-imidazolyl]phenyl]guanidine, N-cyano-N''-methyl-N''''-[2-[5(4)-methyl-4(5)-imidazolyl]phenyl]guanidine and 3-amino-4-[[3-[5(4)-methyl-4(5)-imidazolyl]phenyl]-amino]-1,2,5-thiadiazole 1-oxide] were evaluated for antagonism of the dimaprit-stimulated chronotropic response in the guinea pig atrium and inhibition of histamine stimulated secretion of gastric acid in the dog. In both series, biological activity is markedly dependent on the m-phenylene regioisomers. Histamine H2-receptor activity is retained in both series; however, in the tiotidine series, gastric antisecretory activity is significantly improved. Regardless of the end group, N-cyanoguanidine (1b), 1,1-diamino-2-nitroethene (2b) or 3,4-diamino-1,2,5-thiadiazole 1-oxide (3b and 4b), each 3-(2-guanidino-4-thiazolyl)phenyl analog was ca. [around] 8 and 90 times more potent i.v. than tiotidine and cimetidine, respectively. The electronic influences of the phenylene unit on biological activity were also evaluated. The geometric constraints imposed by the m-phenylene connecting element were evidently more important than electronic factors in binding events at the histamine H2 receptor.