Discovery of potent cholecystokinin-2 receptor antagonists: elucidation of key pharmacophore elements by X-ray crystallographic and NMR conformational analysis.

Abstract A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (p K i  = 7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, 1 H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.