CCK2R antagonists: from SAR to clinical trials

The widespread involvement of the cholecystokinin-2/Gastrin receptor (CCK₂R) in multiple (patho)physiological processes has propelled extensive searches for nonpeptide small-molecule CCK₂R antagonists. For the past three decades, considerable research has yielded numerous chemically heterogeneous compounds. None of these entered into the clinic, mainly because of inadequate biological effects. However, it appears that the ultimate goal of a clinically useful CCK₂R antagonist is now just around the corner, with the most promising compounds, netazepide and nastorazepide, now in Phase II clinical trials. Here, we illustrate the structure-activity relationships (SARs) of stablished CCK₂R antagonists of various structural classes, and the most recent proof-of-concept studies where new applicabilities of CCK₂R antagonists as visualizing agents are presented.