205063-51-0Relevant articles and documents
Novel nonpeptide CCK-B antagonists: Design and development of quinazolinone derivatives as potent, selective, and orally active CCK-B antagonists
Padia, Janak K.,Field, Mark,Hinton, Joanna,Meecham, Ken,Pablo, Julius,Pinnock, Rob,Roth, Bruce D.,Singh, Lakhbir,Suman-Chauhan, Nirmala,Trivedi, Bharat K.,Webdale, Louise
, p. 1042 - 1049 (2007/10/03)
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.
