Optimization of 1,3,4-benzotriazepine-based CCK(2) antagonists to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion.
J Med Chem
; 50(13): 3101-12, 2007 Jun 28.
Article
em En
| MEDLINE
| ID: mdl-17536796
ABSTRACT
Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pentagastrina
/
Benzodiazepinas
/
Receptor de Colecistocinina B
/
Ácido Gástrico
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Reino Unido