Cholecystokinin (CCK) is a polypeptide hormone which occurs in numerous molecular forms throughout the peripheral and central nervous systems. CCK exerts a variety of actions on peripheral organs, such as regulating pancreatic secretion, gut motility, and gall bladder contraction. In addition CCK may function as a neurotransmitter or neuromodulator in the central nervous system.* 1•2 The actions of CCK are mediated by two receptor subtypes designated as CCKa and CCKb.3 The CCKb receptor subtype also displays ligand specificities similar to the stomach gastrin receptor.4•6The benzodiazepine series of non-peptide CCK receptor antagonists, which was designed from the natural product asperlicin,6 has been well documented. The high affinity and potent CCKa receptor selective antagonist MK-3297 and the CCKb receptor selective antagonist L-365,2608•9 (1) resulted from this work. One factor which determined CCK receptor subtype selectivity in this series was the C3-stereochemistry of the benzodiazepine ring system, the (3R)-enantiomer generally providing CCKb receptor selectivity. Recent studies have shown that the C5-phenyl moiety of the core benzodiazepine structure could be replaced by C5-cycloalkyl groups, a modification which retained CCKb affinity and selectivity.10 In particular, the C5-cyclohexyl analog (2) displayed sub-nanomolar CCKb receptor affinity (IC50, 0.28 nM), with improved selectivity (CCKa/CCKb = 6500) compared to L-365,260. The aqueous solubility of crystalline 1 has been measured as <0.002 mg/mL in the pH range 3-7.4, and pharmacokinetic studies11 have shown that 1 displayed limited bioavailability in rat, dog, and monkey when dosed orally using 0.5% methylcellulose as a vehicle. This suggests that 1 would not be a suitable chemical entity for oral administration in humans as a simple tablet formulation.12 The cyclohexyl analog 2 would be expected to suffer from the same drawback.The objective of this present study, therefore, was the design, synthesis, and evaluation of CCKb receptor antagonists which would retain the excellent binding and selectivity characteristics of 2, while embodying a watersolubilizing handle. In an accompanying Communication, we report on a series of acidic CCKb receptor antagonists which fulfill these criteria.

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