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

Bioorganic & medicinal chemistry letters 2010 Jul 8; In press

Schlegel K KA, Yang Z ZQ, Reger T TS, Shu Y, Cube R, Rittle K KE, Bondiskey P, Bock M MG, Hartman G GD, Tang C, Ballard J, Kuo Y, Prueksaritanont T, Nuss C CE, Doran S SM, Fox S SV, Garson S SL, Kraus R RL, Li Y, Uebele V VN, Renger J JJ, Barrow J JC

Department of Medicinal Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, USA.

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.

Keywords: T-type calcium channel antagonist epilepsy sleep