title: 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 (pK(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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Drug Discover, 3210 Merryfield Row, San Diego, CA 92121, USA. mrosen1@prdus.jnj.com
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rosen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hack
authors.forename: Brett D
authors.initials: BD
authors.lastname: Allison
authors.forename: Victor K
authors.initials: VK
authors.lastname: Phuong
authors.forename: Craig R
authors.initials: CR
authors.lastname: Woods
authors.forename: Magda F
authors.initials: MF
authors.lastname: Morton
authors.forename: Clodagh E
authors.initials: CE
authors.lastname: Prendergast
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Barrett
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Lina
authors.initials: L
authors.lastname: Li
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wu
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Freedman
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Shankley
authors.forename: Michael H
authors.initials: MH
authors.lastname: Rabinowitz
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D043886:Receptor, Cholecystokinin A / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D013449:Sulfonamides