1. Optimization of 1,3,4-Benzotriazepine-Based CCK2Antagonists to Obtain Potent, Orally Active Inhibitors of Gastrin-Mediated Gastric Acid Secretion.
- Author
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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, Sonia P. Roberts, Mark E. Shaxted, John Spencer, Katherine I. M. Steel, David A. Sykes, Martin K. Walker, Gillian F. Watt, Laurence Wright, and Paul T. Wright
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CHOLECYSTOKININ , *GASTRIC acid , *ACETAMIDE , *RADIOLIGAND assay - Abstract
Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2receptors and high selectivity over CCK1receptors 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- 1,2,4oxadiazol-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. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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