NOVEL NONPEPTIDE CCK-B ANTAGONISTS - DESIGN AND DEVELOPMENT OF QUINAZOLINONE DERIVATIVES AS POTENT, SELECTIVE, AND ORALLY-ACTIVE CCK-E ANTAGONISTS

We have designed a novel series of CCK-B receptor antagonists by combi ning key pharmacophores, an arylurea moiety of 1 and a quinazolinone r ing of 3, from two known series. Our earlier studies showed that compo unds with methylene linkers in our ''target'' produced moderate bindin g affinity and selectivity for CCK-B receptors, whereas its higher and lower homologues resulted in loss of affinity. Introduction of -NH- a s a linker dramatically enhanced binding affinity and selectivity for CCK-B receptors, thus providing several compounds with single-digit na nomolar binding affinity and excellent selectivity. Analogous to the e arlier studies of the series of quinazolinone derivatives 3, we also f ound 3-isopropoxyphenyl as a preferred substitution on the N-3 quinazo linone. Electron-withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B potency. Representative compounds of this ser ies were tested in the functional assay and showed pure antagonist pro files. Compounds 51 and 61 were orally active in the elevated rat X-ma ze test. These compounds were also evaluated for their pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.