- Discovery of potent cholecystokinin-2 receptor antagonists: Elucidation of key pharmacophore elements by X-ray crystallographic and NMR conformational analysis
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A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pKi = 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, 1H 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.
- Rosen, Mark D.,Hack, Michael D.,Allison, Brett D.,Phuong, Victor K.,Woods, Craig R.,Morton, Magda F.,Prendergast, Clodagh E.,Barrett, Terrance D.,Schubert, Carsten,Li, Lina,Wu, Xiaodong,Wu, Jiejun,Freedman, Jamie M.,Shankley, Nigel P.,Rabinowitz, Michael H.
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p. 3917 - 3925
(2008/12/20)
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