Journal of Medicinal Chemistry · 1994 · 73 citations · 0 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignStructure-activity RelationshipsSynthetic Medicinal ChemistryDrug ReceptorsDrug-receptor InteractionsLigand BindingReceptor PharmacologyReceptor-ligand InteractionsStructure-activity Relationship AnalysisCholecystokinin PharmacologyCompetitive Receptor AntagonismLigand Design For ReceptorsMacrocyclic ReceptorsPrivileged Structure-based DesignReceptor Binding OptimizationStructure-based Ligand Design
A series of 5-phenyl-3-ureidobenzazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 4-phenyl-1-tetralone as a key step. Structure-activity relationship studies revealed the importance of the 5-phenyl group for potent and selective CCK-B affinity. Addition of an 8-methyl substituent and resolution provided the potent (CCK-B IC50 = 0.48 nM) CCK-B antagonist 4. The role of the 5-phenyl group as part of a "privileged structure" for high-affinity receptor antagonism is discussed.