Cholecystokinin antagonists. Synthesis of asperlicin analogs with improved potency and water solubility

• Published in: Journal of medicinal chemistry Vol. 29; no. 10; pp. 1941 - 1945
• Main Authors: Bock, Mark G, DiPardo, Robert M, Rittle, Kenneth E, Evans, Ben E, Freidinger, Roger M, Veber, Daniel F, Chang, Raymond S. L, Chen, Tsing Bau, Keegan, Maureen E, Lotti, Victor J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.10.1986
• Subjects: Animals; Benzodiazepinones - chemical synthesis; Benzodiazepinones - pharmacology; Chemistry; Cholecystokinin - antagonists & inhibitors; Exact sciences and technology; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; In Vitro Techniques; Organic chemistry; Preparations and properties; Rats; Receptors, Cholecystokinin - drug effects; Solubility; Structure-Activity Relationship; Water; Aminoamide; Angular nitrogen heterocycle; Lactam; Solubility; Urethane; Tetracyclic compound; Tricyclic compound; Biological activity; Diester; Dicarboxylic acid; Aromatic compound; Antagonist; Cholecystokinin
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00160a024

Seventeen analogues of the selective, competitive cholecystokinin (CCK) antagonist asperlicin 1 were prepared. These compounds were tested as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. Compounds 4, 7, and 8 were more potent than asperlicin on the pancreatic CCK receptor. One analogue, 17, displayed potency equivalent to asperlicin on the pancreas CCK receptor and showed a marked improvement in aqueous solubility, thereby facilitating the use of this class of CCK antagonists in physiological and pharmacological studies.