Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with decreased hydrophobicity

Article abstract of DOI:10.1016/S0968-0896(97)00074-6

In order to study structure-activity relationships of the previously reported dual histamine H₂ and gastrin receptor antagonists and also to improve their low oral absorbability, we tried two chemical modifications. One tried to decrease the high hydrophobicity of the parent hybrid compounds to an appropriate level by incorporating a hydrophilic group into the molecule and the other by replacing the more hydrophobic groups with less hydrophobic ones. The former compounds (type I) involved hybrid compounds with a hydroxyl group at a position of a spacer, a piperidine moiety of H₂A, or a phenyl ring at the C₅ of the benzodiazepine skeleton as well as those with a free carboxyl group in the piperidine moiety of H₂A. The latter (type II) involved hybrid compounds with the C₅-phenyl group replaced with either a methyl group or hydrogen atom. Among them, only a type I compound, ({2-[3-(3-piperidin-1 -ylmethylphenoxy)propylcarbamoyl]ethylcarbamoyl}methyl)carbamic acid 3-{3-[5-(3-hydroxy- phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]ureido}benzyl ester (18), showed potent dual histamine H₂ and gastrin receptor antagonistic activity, whereas others resulted in a significant decrease of histamine H₂ receptor antagonistic activity. The in vivo gastric acid antisecretory activity of 18 evaluated by Schild's rat method, however, did not suggest any notable improvement in oral absorbability.