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
  • 1. Department of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA. [email protected]
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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