New 1,4-Benzodiazepin-2-one Derivatives as Gastrin/Cholecystokinin-B Antagonists

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A novel series of 1-aroylmethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivatives was prepared and evaluated for activity as gastrin/cholecystokinin (CCK)-B receptor antagonists. In vitro binding studies showed that some derivatives exhibited potent affinity for gastrin/CCK-B receptor and high selectivity over peripheral CCK (CCK-A) receptor. Furthermore, these compounds potently inhibited pentagastrin-induced gastric acid secretion upon intravenous administration in an in vivo model in rats. Structure-activity relationship studies of this series suggested that 1-[(R)-2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (35b, YM022) was the optimal compound with IC_<50> values of 0.17,0.11 and 150nM for gastrin, CCK-B and CCK-A receptors, respectively, and an ED_<50> value of 9.5nmol/kg (i.v.) in rats. The absolute configuration of the precursor of YM022,an (R)-3-amino-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivative ((R)-25), was determined by X-ray crystallographic analysis of its (S)-mandelate.It would be expected that YM022,a potent and selective gastrin/CCK-B receptor antagonist, inhibits gastric acid secretion without inducing gastrin-mediated side-effects such as hypergastrinemia and hyperplasia of oxyntic mucosa.
社団法人日本薬学会の論文
1995-12-15