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

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. UebeleJohn J. Renger, James C. Barrow

Research output: Contribution to journalArticlepeer-review

Abstract

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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)5147-5152
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number17
DOIs
StatePublished - Sep 1 2010
Externally publishedYes

Keywords

  • Calcium channel antagonists
  • Epilepsy
  • Quinazolin-2-ones
  • T-Type calcium channel

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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