The anthranilic acid diamides represent the most recent class of nonpeptide CCK1 receptor (CCK1-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using non-proteinogenic aminoacids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK1-R affinity and 15-fold for the human CCK1-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (Comp.6) exhibited a nanomolar range affinity towards the human CCK1-R and was at least 400-fold selective for the CCK1-R over the CCK2-R. Molecular docking in the modeled CCK1-R and its validation by site-directed mutagenesis experiments showed that 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK1R antagonists.
