CCK2R antagonists: from SAR to clinical trials

• Published in: Drug discovery today 2020-08, Vol.25 (8), p.1322-1336
• Main Authors: Novak, Doroteja, Anderluh, Marko, Kolenc Peitl, Petra
• Format: Article
• Language: English
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2020.05.008

•The CCK2 receptor is involved in numerous (patho)physiological processes.•Many CCK2 receptor antagonists have shown promising results in in-vivo animal models.•High attrition rates are seen in clinical settings due to off-target effects.•Netazepide (YF476) and nastorazepide (Z-360) are in Phase II clinical trials.•Nastorazepide (Z-360) serves as a lead compound for development of imaging agents. 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. The quest for the first clinically useful CCK2R antagonist: is it a never-ending story, or are we on the verge of a breakthrough?