(Imidazolylphenyl)formamidines. A structurally novel class of potent histamine H2 receptor antagonists

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Abstract
Structure-activity considerations of N.alpha.-guanylhistamine, the first compound found with detectable H2-antagonist activity, led to the synthesis of a series of conformationally rigid guanylhistamine analogs, i.e., (imidazolylphenyl)guanidines, imidazolylbenzamidines and (imidazolylphenyl)formamidines. In the guanidine and benzamidine classes, the m-substituted derivatives [e.g., N-methyl-N''-(3-1H-imidazol-4-ylphenyl)guanidine dihydrochloride (4)] possessed H2-antagonist activity, whereas in the class of formamidines, only the p-substituted derivative was active. A subsequent increase in the size of the substituent at the formamidino group led to compounds (15-20) [(imidazolylphenyl)formamidines] of high H2-antagonist affinity, which was related to the gastric antisecretory effect. Members of this structurally novel class of H2 antagonists were 20- to 50-fold more potent than cimetidine both in vitro and in vivo. Structure-activity relationships are discussed in terms of ionization properties, partitioning behavior, conformational aspects of the selected compound 17 [N-isopropyl-N''-(4-1H-imidazol-4-ylphenyl)formamidine dihydrochloride], and of possible modes of interaction with the histamine H2 receptor. The formamidine moiety was an important structural feature and H2-antagonist activity requires correct steric and electronic properties. Compound 17 (DA 4577), owing to its pharmacological profile and demonstrated safety in animals [rats] was selected to be clinically investigated.

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