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

  • ACS Med Chem Lett. 2010 Aug 24;1(9):504-9. doi: 10.1021/ml100170e.
Zhi-Qiang Yang  1 ,  Kelly-Ann S Schlegel  1 ,  Youheng Shu  1 ,  Thomas S Reger  1 ,  Rowena Cube  1 ,  Christa Mattern  1 ,  Paul J Coleman  1 ,  Jim Small  1 ,  George D Hartman  1 ,  Jeanine Ballard  2 ,  Cuyue Tang  2 ,  Yuhsin Kuo  2 ,  Thomayant Prueksaritanont  2 ,  Cindy E Nuss  3 ,  Scott Doran  3 ,  Steve V Fox  3 ,  Susan L Garson  3 ,  Yuxing Li  3 ,  Richard L Kraus  3 ,  Victor N Uebele  3 ,  Adekemi B Taylor  2 ,  Wei Zeng  2 ,  Wei Fang  2 ,  Cynthia Chavez-Eng  2 ,  Matthew D Troyer  4 ,  Julie Ann Luk  4 ,  Tine Laethem  4 ,  William O Cook  5 ,  John J Renger  3 ,  James C Barrow  1
Affiliations
  • 1. Departments of Medicinal Chemistry.
  • 2. Drug Metabolism and Pharmacokinetics.
  • 3. Depression and Circadian Disorders.
  • 4. Clinical Pharmacology.
  • 5. Toxicology Sciences.
PMID: 24900239 DOI: 10.1021/ml100170e
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.

Keywords
Calcium channel antagonists; T-type calcium channels; electrocorticogram; pharmacokinetics; sleep.
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