2. Academic Validation
  3. Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents

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

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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