title: New 1,4-benzodiazepin-2-one derivatives as gastrin/cholecystokinin-B antagonists.
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 as hypergastrinemia and hyperplasia of oxyntic mucosa.
authors.affiliation: Neuroscience-Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Tsukuba City, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Satoh
authors.forename: Y
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.forename: A
authors.initials: A
authors.lastname: Nishida
authors.forename: K
authors.initials: K
authors.lastname: Miyata
authors.forename: M
authors.initials: M
authors.lastname: Ohta
authors.forename: T
authors.initials: T
authors.lastname: Mase
authors.forename: K
authors.initials: K
authors.lastname: Murase
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D005744:Gastric Acid / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000777:Anesthetics; D001570:Benzodiazepinones; D006727:Hormone Antagonists; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C087260:YM 022