Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists.
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.
Schlegel
Kelly-Ann S
KA
Department of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA. kelly_ann_bieber@merck.com
Yang
Zhi-Qiang
ZQ
Reger
Thomas S
TS
Shu
Youheng
Y
Cube
Rowena
R
Rittle
Kenneth E
KE
Bondiskey
Phung
P
Bock
Mark G
MG
Hartman
George D
GD
Tang
Cuyue
C
Ballard
Jeanine
J
Kuo
Yuhsin
Y
Prueksaritanont
Thomayant
T
Nuss
Cindy E
CE
Doran
Scott M
SM
Fox
Steven V
SV
Garson
Susan L
SL
Kraus
Richard L
RL
Li
Yuxing
Y
Uebele
Victor N
VN
Renger
John J
JJ
Barrow
James C
JC
D000818:Animals; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D055808:Drug Discovery; D000882:Haplorhini; D006801:Humans; D052999:Quinazolinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D052999:Quinazolinones