title: Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA. kelly_ann_bieber@merck.com
authors.forename: Kelly-Ann S
authors.initials: KA
authors.lastname: Schlegel
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yang
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Reger
authors.forename: Youheng
authors.initials: Y
authors.lastname: Shu
authors.forename: Rowena
authors.initials: R
authors.lastname: Cube
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Rittle
authors.forename: Phung
authors.initials: P
authors.lastname: Bondiskey
authors.forename: Mark G
authors.initials: MG
authors.lastname: Bock
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.forename: Jeanine
authors.initials: J
authors.lastname: Ballard
authors.forename: Yuhsin
authors.initials: Y
authors.lastname: Kuo
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Cindy E
authors.initials: CE
authors.lastname: Nuss
authors.forename: Scott M
authors.initials: SM
authors.lastname: Doran
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kraus
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
mesh_terms: 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
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D052999:Quinazolinones