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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 ?M with an apparent terminal half-life of 3.0 ± 1.1 h.

SUBMITTER: Yang ZQ

PROVIDER: S-EPMC4007914 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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

Yang Zhi-Qiang ZQ Schlegel Kelly-Ann S KA Shu Youheng Y Reger Thomas S TS Cube Rowena R Mattern Christa C Coleman Paul J PJ Small Jim J Hartman George D GD Ballard Jeanine J Tang Cuyue C Kuo Yuhsin Y Prueksaritanont Thomayant T Nuss Cindy E CE Doran Scott S Fox Steve V SV Garson Susan L SL Li Yuxing Y Kraus Richard L RL Uebele Victor N VN Taylor Adekemi B AB Zeng Wei W Fang Wei W Chavez-Eng Cynthia C Troyer Matthew D MD Luk Julie Ann JA Laethem Tine T Cook William O WO Renger John J JJ Barrow James C JC

ACS medicinal chemistry letters 20100824 9

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 telemetr ...[more]

PMID: 24900239

Dataset Information

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

Publications

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

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