5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c] pyrimidine-based potentand selective CCK1 receptor antagonists: Structure-activity relationship studies on the central 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold

To further define the pharmacophore of the potent and selective 5-(tryptoph yl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based CCK1 receptor antag onists the electronic and topographic properties of the central 1, 3-dioxop erhydro-pyrido[1,2-c]pyrimidine scaffold have been modified. With this aim, the 1- and 3-oxo groups have been replaced by the thioxo- and deoxi-analog ues, and the fused piperidine ring has been contracted to the corresponding pyrrolidine moiety. The results of the evaluation of the new analogues as CCK receptor ligands, in rat pancreas and cerebral cortex preparations, sho wed that, whereas replacement of oxygen with sulfur is allowed, reduction o f the 1- or 3-oxo groups or the contraction of the fused piperidine ring le ad to the complete loss of binding affinity at CCK1 receptors. The thioxo-a nalogues 5a, 8a, 12a, and 12b showed functional CCK1 antagonist activity, i nhibiting the CCK-8-stimulated amylase release from pancreatic acinar cells . The 1-thioxo analogue 5a, with subnanomolar affinity (IC50 = 0.09 x 10(-9 ) M), was found to be the most potent and selective compound within the fam ily of 5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based C CK1 antagonists.