Cholecystokinin Antagonists: Fluorinated 5-Hydroxy-5-Aryl-Pyrrol-2-Ones as Experimental Agents for Brain, Colon and Pancreatic Cancer

Submit Manuscript | http://medcraveonline.com Asperlicin was the first non-peptidal lead structure from nature [12] and analogues thereof were studied as CCK ligands [13]. Simplification of this lead structure by Merck led to Devazepide [14], a potent CCK1 selective cholecystokinin antagonist (Figure 1), containing a 1,4-benzodiazepine template and an indole moiety. Proglumide [15] was the first glutamic acid based agent, marketed as Milid for the treatment of ulcer. Lorglumide, a derivative of proglumide [16], (Figure 1) is one of several CCK receptor antagonists [17] and served as experimental standard. The indolyl amide of devazepide was replaced by a urea linkage and Merck’s L-365,260 resulted in a CCK2 selective antagonist [18]. Z-360 is a CCK2 -gastrin receptor antagonist and progressed into phase 2 trial with pancreatic cancer [19]. Z-360 is the most recent derivative derived from this original lead structure, with improved selectivity and bioavailability.