Novel Nonpeptide CCK-B Antagonists:  Design and Development of Quinazolinone Derivatives as Potent, Selective, and Orally Active CCK-B Antagonists

• Published in: Journal of medicinal chemistry 1998-03, Vol.41 (7), p.1042-1049
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Cholecystokinin - antagonists & inhibitors; Male; Maze Learning - drug effects; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Rats; Rats, Wistar
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970373j

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.