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

Chemical & Pharmaceutical Bulletin
M SatohK Murase

Abstract

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-(2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phe nyl-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 that YM022, a potent and selective gastrin CCK-B receptor antagonist, inhibits gastric acid secretion without inducing gastrin-mediated side effects such ...Continue Reading

Citations

Nov 4, 2000·Expert Opinion on Investigational Drugs·P de TullioB Pirotte
Mar 16, 2006·The Journal of Pharmacy and Pharmacology·Eric LattmannJintana Sattayasai
Jun 6, 2003·Medicinal Research Reviews·Rosario Herranz
Jul 4, 2006·Physiological Reviews·Marlène DufresneDaniel Fourmy

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