Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents

Zhi Qiang Yang, Kelly Ann S. Schlegel, Youheng Shu, Thomas S. Reger, Rowena Cube, Christa Mattern, Paul J. Coleman, Jim Small, George D. Hartman, Jeanine Ballard, Cuyue Tang, Yuhsin Kuo, Thomayant Prueksaritanont, Cindy E. Nuss, Scott Doran, Steve V. Fox, Susan L. Garson, Yuxing Li, Richard L. Kraus, Victor N. UebeleAdekemi B. Taylor, Wei Zeng, Wei Fang, Cynthia Chavez-Eng, Matthew D. Troyer, Julie Ann Luk, Tine Laethem, William O. Cook, John J. Renger, James C. Barrow

Research output: Contribution to journalArticlepeer-review

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 Cmax of 1.82 ± 0.274 μM with an apparent terminal half-life of 3.0 ± 1.1 h.

Original languageEnglish (US)
Pages (from-to)504-509
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume1
Issue number9
DOIs
StatePublished - Dec 9 2010
Externally publishedYes

Keywords

  • Calcium channel antagonists
  • T-type calcium channels
  • electrocorticogram
  • pharmacokinetics
  • sleep

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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