Potent and subtype-selective CCK-B/gastrin receptor antagonists: 2,4-dioxo-1,5-benzodiazepines with a plane of symmetry

A series of CCK-B/gastrin receptor antagonists, 2,4-dioxo-1,5-benzodiazepine derivatives with a plane of symmetry, were designed, synthesized, and evaluated for antagonistic activity. Structure-activity relationship studies revealed that carbonylmethyl groups at both N-1 and N-5 positions and hydrop...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 1997-07, Vol.5 (7), p.1433-1446
Main Authors: Hagishita, Sanji, Seno, Kaoru, Kamata, Susumu, Haga, Nobuhiro, Ishihara, Yasunobu, Ishikawa, Michio, Shimamura, Mayumi
Format: Article
Language:English
Subjects:
Animals
Benzodiazepines - chemistry
Benzodiazepines - metabolism
Benzodiazepines - pharmacology
Binding, Competitive
Guinea Pigs
Male
Mice
Mice, Inbred Strains
Molecular Conformation
Rats
Rats, Sprague-Dawley
Receptor, Cholecystokinin A
Receptor, Cholecystokinin B
Receptors, Cholecystokinin - antagonists & inhibitors
Receptors, Cholecystokinin - metabolism
Structure-Activity Relationship
Substrate Specificity
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Summary:A series of CCK-B/gastrin receptor antagonists, 2,4-dioxo-1,5-benzodiazepine derivatives with a plane of symmetry, were designed, synthesized, and evaluated for antagonistic activity. Structure-activity relationship studies revealed that carbonylmethyl groups at both N-1 and N-5 positions and hydrophilic groups, such as the carboxyl group on the benzene ring attached to the ureido group at the C-3 position, brought about potent affinity and subtype selectivity for CCK-B/gastrin receptors. Several compounds showed excellent in vivo inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats. Graphic
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(97)00083-7