Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists

Kelly Ann S. Schlegel; Zhi Qiang Yang; Thomas S. Reger; Youheng Shu; Rowena Cube; Kenneth E. Rittle; Phung Bondiskey; Mark G. Bock; George D. Hartman; Cuyue Tang; Jeanine Ballard; Yuhsin Kuo; Thomayant Prueksaritanont; Cindy E. Nuss; Scott M. Doran; Steven V. Fox; Susan L. Garson; Richard L. Kraus; Yuxing Li; Victor N. Uebele; John J. Renger; James C. Barrow

doi:10.1016/j.bmcl.2010.07.010

Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists

Kelly Ann S. Schlegel, Zhi Qiang Yang, Thomas S. Reger, Youheng Shu, Rowena Cube, Kenneth E. Rittle, Phung Bondiskey, Mark G. Bock, George D. Hartman, Cuyue Tang, Jeanine Ballard, Yuhsin Kuo, Thomayant Prueksaritanont, Cindy E. Nuss, Scott M. Doran, Steven V. Fox, Susan L. Garson, Richard L. Kraus, Yuxing Li, Victor N. UebeleJohn J. Renger, James C. Barrow

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22 Scopus citations

Abstract

The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca²⁺ channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.

Original language	English (US)
Pages (from-to)	5147-5152
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2010.07.010
State	Published - Sep 1 2010
Externally published	Yes

Keywords

Calcium channel antagonists
Epilepsy
Quinazolin-2-ones
T-Type calcium channel

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2010.07.010

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Schlegel, K. A. S., Yang, Z. Q., Reger, T. S., Shu, Y., Cube, R., Rittle, K. E., Bondiskey, P., Bock, M. G., Hartman, G. D., Tang, C., Ballard, J., Kuo, Y., Prueksaritanont, T., Nuss, C. E., Doran, S. M., Fox, S. V., Garson, S. L., Kraus, R. L., Li, Y., ... Barrow, J. C. (2010). Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists. Bioorganic and Medicinal Chemistry Letters, 20(17), 5147-5152. https://doi.org/10.1016/j.bmcl.2010.07.010

Schlegel, KAS, Yang, ZQ, Reger, TS, Shu, Y, Cube, R, Rittle, KE, Bondiskey, P, Bock, MG, Hartman, GD, Tang, C, Ballard, J, Kuo, Y, Prueksaritanont, T, Nuss, CE, Doran, SM, Fox, SV, Garson, SL, Kraus, RL, Li, Y, Uebele, VN, Renger, JJ & Barrow, JC 2010, 'Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 17, pp. 5147-5152. https://doi.org/10.1016/j.bmcl.2010.07.010

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abstract = "The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca2+ channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.",

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AU - Schlegel, Kelly Ann S.

AU - Yang, Zhi Qiang

AU - Reger, Thomas S.

AU - Shu, Youheng

AU - Cube, Rowena

AU - Rittle, Kenneth E.

AU - Bondiskey, Phung

AU - Bock, Mark G.

AU - Hartman, George D.

AU - Tang, Cuyue

AU - Ballard, Jeanine

AU - Kuo, Yuhsin

AU - Prueksaritanont, Thomayant

AU - Nuss, Cindy E.

AU - Doran, Scott M.

AU - Fox, Steven V.

AU - Garson, Susan L.

AU - Kraus, Richard L.

AU - Li, Yuxing

AU - Uebele, Victor N.

AU - Renger, John J.

AU - Barrow, James C.

PY - 2010/9/1

Y1 - 2010/9/1

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AB - The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca2+ channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.

KW - Calcium channel antagonists

KW - Epilepsy

KW - Quinazolin-2-ones

KW - T-Type calcium channel

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Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists

Abstract

Keywords

ASJC Scopus subject areas

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