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

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.

A Novel Nonpeptide Ligand for Formyl Peptide Receptor-Like 1

“…However, this nonpeptide ligand for FPRL1 may serve as the nucleus for further structural modifications leading to the discovery of more potent and efficacious agonists. Based on published data, it is possible to develop quinazolinone derivatives with higher binding affinities for cell surface receptors including GPCRs (Oshita et al, 1986;Chern et al, 1993;Padia et al, 1998). The selective activation property of Quin-C1 will be of particular interest for future development of small molecular weight, nonpeptide compounds devoid of cell-stimulating functions associated with tissue injury.…”

Infrared spectra, thermogravimetric analysis and antifungal studies of noval Cr(III), Fe(III) and Cu(II) 2-methyl-quinazolinone complexes

“…Some isolates of G. graminis, F. culmorum, F. moniliforme, F. subglutinans, and of a number of other Fusarium species are able to degrade benzoxazolinone compounds to products which are less inhibitory to fungal growth and also important compounds in chemistry and pharmacology [1][2][3][4][5]. They have drawn much attention due to their broad range of pharmacological properties, which include anticancer, anti-inflammatory, anticonvulsant and antidiuretic activities [6][7][8][9][10]. Consequently, considerable efforts have been made to explore new simple and direct approaches towards the construction of 5(4H)-quinazilinone skeletons such as via amidation of 2-aminobenzonitrile, followed by oxidative ring closure and Pd-catalyzed heterocyclyzation of nitroarenes [11,12].…”

Efficient Room‐Temperature One‐Pot Synthesis of 2‐Amino‐3‐alkyl(3‐aryl)quinazolin‐4(3H)‐ones

“…Among quinazoline-containing compounds, 2-aminoquinazolin-4(3H)-one derivatives are biologically relevant and have been reported as dopamine agonists, [3] histamine H 4 receptor inverse agonists, [4] K ATP channel modulators, [5] CCK-B antagonists, [6] and antitumor, [7] anti-inflammatory, [8] antihypertensive, [9] antihyperglycemic, [10] or antibacterial agents. [11] For these reasons, several methodologies have been developed for their synthesis, which has been recently reviewed.…”