5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK1 receptor antagonists: Structure-activity relationship studies on the substituent at N2-position

To establish structure-activity relationships a new series of analogues of the highly potent and selective CCK1 receptor antagonist (4aS,5R)-2-benzyl- 5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]-pyrimidine (1a) mo dified at N2-position of the central scaffold has been prepared and evaluat ed as CCK receptor ligands. With this aim the N2-benzyl group has been repl aced by methyl, cyclohexyl, aromatic groups, 1-phenylethyl, and 1-carboxy-2 -phenylethyl group. Then, substituents with different electronic and steric properties were introduced into different positions of the phenyl group of analogues 19a and 19b. The results of the CCK receptor binding and in vitr o functional activity evaluation suggest the importance of the lipophilic c haracter and an appropriate spatial orientation of the moiety linked at the N2-position of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine template for p otent and selective binding and antagonist activity at CCK1 receptor subtyp e. The 2-cyclohexyl and (2S)-1-naphthyl derivatives 18a and (2S)-20a have e merged as more potent and selective CCK1 receptor antagonists than the lead compound 1a. Additionally, the results confirm the (4aS,5R)stereochemistry at the central bicyclic skeleton as an essential structural requirement fo r potent binding to this receptor subtype.