Synthesis and biological evaluation of a new reversely linked type of dual histamine H2 and gastrin receptor antagonist

Article abstract of DOI:10.1248/cpb.45.116

In an attempt to improve the low oral absorbability of previously reported dual histamine H₂ and gastrin receptor antagonists, compounds of a different type were synthesized and evaluated for biological activity. These new compounds bear a histamine H₂ receptor antagonist (H₂A) 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 1, 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, shorted a weak but distinct histamine H₂ 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.