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

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• 作者：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 ; Thomayan
• 关键词：Quinazolin-2-ones ; Calcium channel antagonists ; T-Type calcium channel ; Epilepsy
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 September 2010
• 年：2010
• 卷：20
• 期：17
• 页码：5147-5152
• 全文大小：614 K

文摘

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.