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Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists

✍ Scribed by Kelly-Ann S. Schlegel; Zhi-Qiang Yang; Thomas S. Reger; Youheng Shu; Rowena Cube; Kenneth E. Rittle; Phung Bondiskey; Mark G. Bock; George D. Hartman; Cuyue Tang; Jeanine Ballard; Yuhsin Kuo; Thomayant Prueksaritanont; Cindy E. Nuss; Scott M. Doran; Steven V. Fox; Susan L. Garson; Richard L. Kraus; Yuxing Li; Victor N. Uebele; John J. Renger; James C. Barrow

Book ID: 104004626
Publisher: Elsevier Science
Year: 2010
Tongue: English
Weight: 615 KB
Volume: 20
Category: Article
ISSN: 0960-894X
DOI: 10.1016/j.bmcl.2010.07.010

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✦ Synopsis

The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca(2+) channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.

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