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

School of Medicine

Research output: Contribution to journal › Article

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

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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

Cite this

Flaherty, D. P., Simpson, D. S., Miller, M., Maki, B. E., Zou, B., Shi, J., Wu, M., McManus, O. B., Aubé, J., Li, M., & Golden, J. E. (2014). Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold. Bioorganic and Medicinal Chemistry Letters, 24(16), 3968-3973. https://doi.org/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. / 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

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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AU - Shi, Jie

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Access to Document

10.1016/j.bmcl.2014.06.032