CCKR antagonists: from SAR to clinical trials.

The widespread involvement of the cholecystokinin-2/gastrin receptor (CCKR) in multiple (patho)physiological processes has propelled extensive searches for nonpeptide small-molecule CCKR 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 CCKR 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 CCKR antagonists of various structural classes, and the most recent proof-of-concept studies where new applicabilities of CCKR antagonists as visualizing agents are presented.