title: Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.
abstract: A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety. TTA-A8 recently progressed into human clinical trials, and in line with our predictions, preliminary studies (n = 12) with a 20 mg oral dose afforded a high C max of 1.82 ± 0.274 μM with an apparent terminal half-life of 3.0 ± 1.1 h.
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yang
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Kelly-Ann S
authors.initials: KA
authors.lastname: Schlegel
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Youheng
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Reger
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Rowena
authors.initials: R
authors.lastname: Cube
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Christa
authors.initials: C
authors.lastname: Mattern
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Jim
authors.initials: J
authors.lastname: Small
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Ballard
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Yuhsin
authors.initials: Y
authors.lastname: Kuo
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.affiliation: Depression and Circadian Disorders.
authors.forename: Cindy E
authors.initials: CE
authors.lastname: Nuss
authors.affiliation: Depression and Circadian Disorders.
authors.forename: Scott
authors.initials: S
authors.lastname: Doran
authors.affiliation: Depression and Circadian Disorders.
authors.forename: Steve V
authors.initials: SV
authors.lastname: Fox
authors.affiliation: Depression and Circadian Disorders.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Garson
authors.affiliation: Depression and Circadian Disorders.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Depression and Circadian Disorders.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kraus
authors.affiliation: Depression and Circadian Disorders.
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Adekemi B
authors.initials: AB
authors.lastname: Taylor
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Chavez-Eng
authors.affiliation: Clinical Pharmacology.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Troyer
authors.affiliation: Clinical Pharmacology.
authors.forename: Julie Ann
authors.initials: JA
authors.lastname: Luk
authors.affiliation: Clinical Pharmacology.
authors.forename: Tine
authors.initials: T
authors.lastname: Laethem
authors.affiliation: Toxicology Sciences.
authors.forename: William O
authors.initials: WO
authors.lastname: Cook
authors.affiliation: Depression and Circadian Disorders.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
keywords: Calcium channel antagonists; T-type calcium channels; electrocorticogram; pharmacokinetics; sleep