Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold

Daniel P. Flaherty; Denise S. Simpson; Melissa Miller; Brooks E. Maki; Beiyan Zou; Jie Shi; Meng Wu; Owen B. McManus; Jeffrey Aubé; Min Li; Jennifer E. Golden

doi:10.1016/j.bmcl.2014.06.032

Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold

Daniel P. Flaherty, Denise S. Simpson, Melissa Miller, Brooks E. Maki, Beiyan Zou, Jie Shi, Meng Wu, Owen B. McManus, Jeffrey Aubé, Min Li, Jennifer E. Golden

Research output: Contribution to journal › Article › peer-review

Abstract

TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK-3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC ₅₀ = 16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.

Original language	English (US)
Pages (from-to)	3968-3973
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2014.06.032
State	Published - Aug 15 2014
Externally published	Yes

Keywords

Bis-amide
KCNK3
Selective potassium channel inhibitor
TASK1

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.2014.06.032

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Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold. / Flaherty, Daniel P.; Simpson, Denise S.; Miller, Melissa; Maki, Brooks E.; Zou, Beiyan; Shi, Jie; Wu, Meng; McManus, Owen B.; Aubé, Jeffrey; Li, Min; Golden, Jennifer E.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 16, 15.08.2014, p. 3968-3973.

Research output: Contribution to journal › Article › peer-review

Flaherty, Daniel P. ; Simpson, Denise S. ; Miller, Melissa ; Maki, Brooks E. ; Zou, Beiyan ; Shi, Jie ; Wu, Meng ; McManus, Owen B. ; Aubé, Jeffrey ; Li, Min ; Golden, Jennifer E. / Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 16. pp. 3968-3973.

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abstract = "TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK-3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC 50 = 16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.",

keywords = "Bis-amide, KCNK3, Selective potassium channel inhibitor, TASK1",

author = "Flaherty, {Daniel P.} and Simpson, {Denise S.} and Melissa Miller and Maki, {Brooks E.} and Beiyan Zou and Jie Shi and Meng Wu and McManus, {Owen B.} and Jeffrey Aub{\'e} and Min Li and Golden, {Jennifer E.}",

note = "Funding Information: The authors gratefully acknowledge funding from the National Institutes of Health , Grant Numbers R03 MH090849-01 , R03 MH090837-01 and R03 DA031670-01 to M. Wu and partial funding in support of chemistry performed at the University of Kansas Specialized Chemistry Center ( NIH U54HG005031 ) and screening performed at the Johns Hopkins Ion Channel Center (NIH U54 MH084691). The authors also express their sincere appreciation to Dr. Douglas A. Bayliss, University of Virginia Health System, for the donation of stably KCNK3-expressing CHO cells. ",

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AU - Flaherty, Daniel P.

AU - Simpson, Denise S.

AU - Miller, Melissa

AU - Maki, Brooks E.

AU - Zou, Beiyan

AU - Shi, Jie

AU - Wu, Meng

AU - McManus, Owen B.

AU - Aubé, Jeffrey

AU - Li, Min

AU - Golden, Jennifer E.

N1 - Funding Information: The authors gratefully acknowledge funding from the National Institutes of Health , Grant Numbers R03 MH090849-01 , R03 MH090837-01 and R03 DA031670-01 to M. Wu and partial funding in support of chemistry performed at the University of Kansas Specialized Chemistry Center ( NIH U54HG005031 ) and screening performed at the Johns Hopkins Ion Channel Center (NIH U54 MH084691). The authors also express their sincere appreciation to Dr. Douglas A. Bayliss, University of Virginia Health System, for the donation of stably KCNK3-expressing CHO cells.

PY - 2014/8/15

Y1 - 2014/8/15

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Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold

Abstract

Keywords

ASJC Scopus subject areas

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