Cholecystokinin B antagonists. Synthesis and quantitative structure-activity relationships of a series of C-terminal analogues of CI-988

• Published in: Bioorganic & medicinal chemistry 1996-10, Vol.4 (10), p.1733-1745
• Main Authors: Augelli-Szafran, Corinne E., Horwell, David C., Kneen, Clare, Ortwine, Daniel F., Pritchard, Martyn C., Purchase, Terri S., Roth, Bruce D., Trivedi, Bharat K., Hill, David, Suman-Chauhan, Nirmala, Webdale, Louise
• Format: Article
• Language: English
• Subjects: Animals; Hormone Antagonists - chemistry; Hormone Antagonists - pharmacology; Indoles - chemistry; Indoles - pharmacology; Meglumine - analogs & derivatives; Meglumine - chemistry; Meglumine - pharmacology; Mice; Rats; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - antagonists & inhibitors; Receptors, Cholecystokinin - metabolism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/0968-0896(96)00185-X

A study of structure-activity relationships of a series of ‘dipeptoid’ CCK-B receptor antagonists was performed in which variations of the phenyl ring were examined while the [(2-adamantyloxy)carbonyl]-α-methyl- R)-tryptophan moiety of the potent antagonist CI-988 was kept constant. Since the main focus of this study was phenyl substituent variation, series design techniques were employed to insure an adequate spread of physicochemical properties (lipophilic, steric, electronic), as well as positional substitution. A QSAR analysis on sets of 26 and 16 analogues revealed that CCK-B affinity was related to a combination of the overall size and, marginally, lipophilicity of the phenyl ring substituents (i.e., smaller groups were associated with increased potency with an optimum π near zero, respectively). Further exploration revealed that the dimensions and electronics of the para-phenyl substituent could be related to CCK-B affinity. Increased affinity was seen with short, bulky (branched) electron withdrawing groups. Analogs with small para-substituents appeared to be about 1000-fold CCK-B selective, indicating that selectivity for CCK-B binding is sensitive to phenyl ring substitution. The 4-F-phenyl dipeptoid, derived from this study, has extraordinary high affinity at the CCK-B receptor (IC 50 = 0.08 nM) and was also very selective (940-fold CCK-B selective). Consistent with previous reports, ( S)-configuration at the substituted phenethylamide center, a carboxylic acid and the presence of a phenyl ring were found to be associated with increased affinity at both CCK-A and CCK-B receptors. Continued interest in the synthesis of potent, highly selective nonpeptide antagonists for the central (CCK-B) receptor has led to the development of this series of C-terminal analogues of CI-988.