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. Uebele; Adekemi 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

doi:10.1021/ml100170e

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 journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Pages (from-to)	504-509
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	1
Issue number	9
DOIs	https://doi.org/10.1021/ml100170e
State	Published - Dec 9 2010
Externally published	Yes

Keywords

Calcium channel antagonists
T-type calcium channels
electrocorticogram
pharmacokinetics
sleep

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml100170e

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Yang, Z. Q., Schlegel, K. A. S., Shu, Y., Reger, T. S., Cube, R., Mattern, C., Coleman, P. J., Small, J., Hartman, G. D., Ballard, J., Tang, C., Kuo, Y., Prueksaritanont, T., Nuss, C. E., Doran, S., Fox, S. V., Garson, S. L., Li, Y., Kraus, R. L., ... Barrow, J. C. (2010). Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents. ACS Medicinal Chemistry Letters, 1(9), 504-509. https://doi.org/10.1021/ml100170e

Yang, ZQ, Schlegel, KAS, Shu, Y, Reger, TS, Cube, R, Mattern, C, Coleman, PJ, Small, J, Hartman, GD, Ballard, J, Tang, C, Kuo, Y, Prueksaritanont, T, Nuss, CE, Doran, S, Fox, SV, Garson, SL, Li, Y, Kraus, RL, Uebele, VN, Taylor, AB, Zeng, W, Fang, W, Chavez-Eng, C, Troyer, MD, Luk, JA, Laethem, T, Cook, WO, Renger, JJ & Barrow, JC 2010, 'Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents', ACS Medicinal Chemistry Letters, vol. 1, no. 9, pp. 504-509. https://doi.org/10.1021/ml100170e

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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.",

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AU - Ballard, Jeanine

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AU - Fox, Steve V.

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AU - Li, Yuxing

AU - Kraus, Richard L.

AU - Uebele, Victor N.

AU - Taylor, Adekemi B.

AU - Zeng, Wei

AU - Fang, Wei

AU - Chavez-Eng, Cynthia

AU - Troyer, Matthew D.

AU - Luk, Julie Ann

AU - Laethem, Tine

AU - Cook, William O.

AU - Renger, John J.

AU - Barrow, James C.

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

Abstract

Keywords

ASJC Scopus subject areas

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