Optimization of 1,3,4-Benzotriazepine-Based CCK2 Antagonists to Obtain Potent, Orally Active Inhibitors of Gastrin-Mediated Gastric Acid Secretion

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• 作者：Iain M. McDonald ; James W. Black ; Ildiko M. Buck ; David J. Dunstone ; Eric P. Griffin ; Elaine A. Harper ; Robert A. D. Hull ; S. Barret Kalindjian ; Elliot J. Lilley ; Ian D. Linney ; Michael J. Pether ; Son
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：June 28, 2007
• 年：2007
• 卷：50
• 期：13
• 页码：3101 - 3112
• 全文大小：321K
• 年卷期：v.50,no.13(June 28, 2007)
• ISSN：1520-4804

文摘

Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK₂ receptor antagonist, a process of optimizationhas afforded further compounds of this type that maintain the nanomolar affinity for recombinant, humanCCK₂ receptors and high selectivity over CCK₁ receptors observed in the initial lead but display morepotent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely beenachieved without altering their potency at wild-type canine and rat receptors, as judged by their displacementof [¹²⁵I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomachbioassay, 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 themost 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.