Discovery of potent cholecystokinin-2 receptor antagonists: elucidation of key pharmacophore elements by X-ray crystallographic and NMR conformational analysis.
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.
Rosen
Mark D
MD
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Drug Discover, 3210 Merryfield Row, San Diego, CA 92121, USA. mrosen1@prdus.jnj.com
Hack
Michael D
MD
Allison
Brett D
BD
Phuong
Victor K
VK
Woods
Craig R
CR
Morton
Magda F
MF
Prendergast
Clodagh E
CE
Barrett
Terrance D
TD
Schubert
Carsten
C
Li
Lina
L
Wu
Xiaodong
X
Wu
Jiejun
J
Freedman
Jamie M
JM
Shankley
Nigel P
NP
Rabinowitz
Michael H
MH
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
D052160:Benzothiazoles; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D013449:Sulfonamides