Novel nonpeptide CCK-B antagonists: design and development of quinazolinone derivatives as potent, selective, and orally active CCK-B antagonists

Journal of Medicinal Chemistry
J K PadiaL Webdale

Abstract

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.

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Citations

Jul 27, 1999·Current Opinion in Chemical Biology·R M Freidinger
Jun 4, 2015·Bioorganic & Medicinal Chemistry Letters·Benjamin PelcmanHans-Erik Claesson
Jan 15, 2017·Bioorganic & Medicinal Chemistry Letters·Sherine Nabil KhattabAyman El-Faham
Oct 18, 2008·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hanan GeorgeySafinaz Abbas
Jun 6, 2018·Organic & Biomolecular Chemistry·Zhen-Yuan LiaoTun-Cheng Chien
Jun 6, 2003·Medicinal Research Reviews·Rosario Herranz
Aug 17, 2004·Molecular Pharmacology·Masakatsu NanamoriRichard D Ye

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