Synthesis and Biological Evaluation of a New Reversely Linked Type of Dual Histamine H_2 and Gastrin Receptor Antagonist

概要

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In an attempt to improve the low oral absorbability of previously reported dual histamine H_2 and gastrin receptor antagonists, compounds of a different type were synthesized and evaluated for biological activity. These new compounds bear a histamine H_2 receptor antagonist (H_2A) pharmacophore moiety attached to a gastrin receptor antagonist (GA) pharmacophore moiety in a reversed manner, namely the head-to-head manner, different from the previously reported head-to-tail manner. These new hybrid compounds were classified into three types : type I, the regular amide type bearing a roxatidine moiety; type II, the reversed amide type bearing a roxatidine moiety; and type III, hybrid compounds bearing a famotidine moiety directly connected to a GA moiety without a spacer. Among them, only (R)-1-[3-(N'-{4-[2-(N-aminosulfonylamidino)ethylthiomethyl]thiazol-2-yl}guanidinomethyl)phenyl]-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)urea (42), belonging to type III, showed a weak but distinct histamine H_2 receptor-antagonistic activity as well as a modest gastrin receptor-antagonistic activity. Of most importance was the finding that this compound showed a weak but clearly improved in vivo oral antigastric acid secretory activity as a result of the structural changes, including the decreased molecular weight.
公益社団法人日本薬学会の論文
1997-01-15