Structure–Activity Relationships and Characterization of Highly Selective, Long-Acting, Peptide-Based Cholecystokinin 1 Receptor Agonists

A group of peptide-based, long-acting,
stable, highly selective
cholecystokinin 1 receptor (CCK-1R) agonists with the potential to
treat obesity has been identified and characterized, based on systematic
investigation of synthetic CCK-8 analogues with N-terminal linkage
to fatty acids. Sulfated Tyr in such compounds was stable in neutral
buffer. CCK-1R selectivity was achieved mostly by introducing d-N-methyl-Asp instead of Asp at the penultimate
position of CCK-8. Our compound 9 (NN9056) showed similar
in vitro CCK-1R potency and CCK-1R affinity as CCK-8, very high selectivity
for CCK-1R over the cholecystokinin 2 receptor (CCK-2R), strong
reduction of food intake in lean pigs for up to 48 h after one subcutaneous
injection without adverse effects, a plasma half-life of 113 h in
minipigs after intravenous injection, and acceptable chemical stability
in a neutral liquid formulation. In addition, we found a highly selective
CCK-2R agonist by replacing Gly in a CCK-8 derivative with Glu.