New 1,4-benzodiazepin-2-one derivatives as gastrin/cholecystokinin-B antagonists

Article abstract of DOI:10.1248/cpb.43.2159

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 IC₅₀ values of 0.17, 0.11 and 150 nM for gastrin, CCK-B and CCK-A receptors, respectively, and an ED₅₀ value of 9.5 nmol/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 thai 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.

Full text of DOI:10.1248/cpb.43.2159

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