Synthesis and Stereochemical Structure−Activity Relationships of 1,3-Dioxoperhydropyrido[1,2-c]pyrimidine Derivatives:  Potent and Selective Cholecystokinin-A Receptor Antagonists

• Published in: Journal of medicinal chemistry 1997-10, Vol.40 (21), p.3402-3407
• Main Authors: Martín-Martínez, Mercedes, Bartolomé-Nebreda, José M, Gómez-Monterrey, Isabel, González-Muñiz, Rosario, García-López, M. Teresa, Ballaz, Santiago, Barber, Ana, Fortuño, Ana, Del Río, Joaquín, Herranz, Rosario
• Format: Article
• Language: English
• Subjects: Amylases - metabolism; Animals; Benzodiazepinones - pharmacology; Biological and medical sciences; Brain - drug effects; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Devazepide; Digestive system; Medical sciences; Molecular Conformation; Molecular Structure; Pancreas - drug effects; Pharmacology. Drug treatments; Protein Binding - drug effects; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Rats; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - antagonists & inhibitors; Receptors, Cholecystokinin - metabolism; Sincalide - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9703247

The synthesis and stereochemical structure−activity relationships of a new class of potent and selective non-peptide cholecystokinin-A (CCK-A) receptor antagonists based on the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine skeleton are described. The most potent member of this series of eight diastereoisomers, (4aS,5R)-2-benzyl-5-[N-[(tert-butoxycarbonyl)-l-tryptophyl]amino]-1,3-dioxoperhydropyrido[1,2-c]pyrimidine, displays nanomolar CCK-A receptor affinity and higher than 8000-fold potency at the CCK-A than at the CCK-B receptor. As CCK-A antagonist, this compound inhibits the CCK-8-evoked amylase release from pancreatic acinar cells at a low concentration, similar to that of the typical antagonist Devazepide. Highly strict stereochemical requirements for CCK-A receptor binding and selectivity have been found. The l-Trp and the 4a,5-trans disposition of the bicyclic perhydropyrido[1,2-c]pyrimidine are essential for binding potency and selectivity.