Design, Synthesis, and Evaluation of Novel Cholecystokinin B Receptor (CCKBR) Antagonist for Treating Central Nervous System (CNS) Disorders

Chapters 2 and 3 present my efforts to design, synthesize, and characterize a series of novel peptoid analogs as CCKBR antagonists. These new analogs were synthesized and evaluated using calcium flux and competitive radioligand binding assays. The results indicated that several analogs demonstrated excellent potency against CCKBR with IC50 value in the picomolar (pM) range. Further evaluations, including in vitro electrophysiology, pharmacokinetics (PK) studies conducted both in vitro and in vivo, as well as drug safety assessments, showed that the novel CCKBR antagonists exhibited an improved PK profile with no discernible concerns. Among these, CCK-655 displayed a favorable PK profile when administered subcutaneously (SC), making it an excellent candidate for further evaluation.

Chapters 4 and 5 detail the development of novel CCKBR antagonists identified through virtual screening techniques. The screening revealed several new chemical entities that had not previously been reported as CCKBR targets. Subsequent validation allowed me to select one scaffold as the starting point for hit optimization. Utilizing computational techniques such as molecular docking and similarity searches facilitated the design of diverse structures with CCKBR antagonistic properties. Ultimately, I identified a novel scaffold essential for CCKBR antagonism and successfully developed a series of novel CCKBR antagonists.

In summary, this research aims to develop novel CCKBR antagonists for clinical application. I present two strategies for this development: modification of an existing active peptoid scaffold, representing the traditional strategy, and virtual screening as a modern strategy. These two strategies have led to the development of two series of novel CCKBR antagonists, with at least one drug candidate demonstrating considerable promise for clinical use. Future efforts should focus on evaluating the therapeutic effects of these novel CCKBR antagonists in animal disease models, designing and synthesizing additional analogs with improved oral bioavailability, and conducting comprehensive safety evaluations. These steps will advance progress toward the clinical use of these novel CCKBR antagonists.