title: Synthesis and biological evaluation of a new reversely linked type of dual histamine H2 and gastrin receptor antagonist.
abstract: 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 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) ure a (42), belonging to type III, showed 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.
authors.affiliation: Discovery Research Laboratories II, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawanishi
authors.forename: S
authors.initials: S
authors.lastname: Ishihara
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Tsushima
authors.forename: S
authors.initials: S
authors.lastname: Hagishita
authors.forename: M
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D001569:Benzodiazepines / Q000008:administration & dosage / Q000138:chemical synthesis*; D015195:Drug Design; D015738:Famotidine / Q000737:chemistry; D005744:Gastric Acid / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000737:chemistry*; D008970:Molecular Weight; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
chemical_list: C104689:1-(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; D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; D015738:Famotidine; C053742:roxatidine acetate