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

Abstract

A novel series of 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-methylpheny) 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 derivative 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. © 1995, The Pharmaceutical Society of Japan. All rights reserved.