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

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

  • Bioorg Med Chem Lett. 2010 Sep 1;20(17):5147-52. doi: 10.1016/j.bmcl.2010.07.010.
Kelly-Ann S Schlegel 1,  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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA. kelly_ann_bieber@merck.com
PMID: 20673719 DOI: 10.1016/j.bmcl.2010.07.010
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 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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