Novel nonpeptide CCK-B antagonists: design and development of quinazolinone derivatives as potent, selective, and orally active CCK-B antagonists.
We have designed a novel series of CCK-B receptor antagonists by combining key pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our earlier studies showed that compounds with methylene linkers in our "target" produced moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and lower homologues resulted in loss of affinity. Introduction of -NH- as a linker dramatically enhanced binding affinity and selectivity for CCK-B receptors, thus providing several compounds with single-digit nanomolar binding affinity and excellent selectivity. Analogous to the earlier studies of the series of quinazolinone derivatives 3, we also found 3-isopropoxyphenyl as a preferred substitution on the N-3 quinazolinone. Electron-withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B potency. Representative compounds of this series were tested in the functional assay and showed pure antagonist profiles. Compounds 51 and 61 were orally active in the elevated rat X-maze test. These compounds were also evaluated for their pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.
Padia
J K
JK
Department of Chemistry, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105, USA.
Field
M
M
Hinton
J
J
Meecham
K
K
Pablo
J
J
Pinnock
R
R
Roth
B D
BD
Singh
L
L
Suman-Chauhan
N
N
Trivedi
B K
BK
Webdale
L
L
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D002766:Cholecystokinin