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.