Cholecystokinin antagonists. Synthesis and biological evaluation of 3-substituted benzolactams

A series of 1,3-substituted benzolactams are reported that are potent nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK). Design considerations were based upon the natural product CCK antagonist asperlicin and the potent benzodiazepine antagonist series exemplified by L-364,718 (1). Compound 19, the most potent compound in the benzolactam series, had an IC50 = 3 nM for inhibition of binding of 125I-CCK-8 to CCK receptors in rat pancreatic tissue, and its racemic analogue 8 was found to be orally active in inhibiting CCK-induced gastric emptying in mice, with an ED50 = 2.6 mg/kg po. The effects of ring size, substitution at positions 1 and 3, and stereochemistry at position 3 are discussed. Conformational studies of compound 19 and L-364,718 have delineated similarities that these molecules share in their core conformations and substituent orientations.