Journal article
D. Ramírez, M. Mejia-Gutierrez, B. Insuasty, S. Rinné, Aytuğ K. Kiper, Magdalena Platzk, Thomas Müller, N. Decher, J. Quiroga, P. De-la-Torre, W. González
Molecules, 2021
Molecules, 2021
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APA
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Ramírez, D., Mejia-Gutierrez, M., Insuasty, B., Rinné, S., Kiper, A. K., Platzk, M., … González, W. (2021). 5-(Indol-2-yl)pyrazolo[3,4-b]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis. Molecules.
Chicago/Turabian
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Ramírez, D., M. Mejia-Gutierrez, B. Insuasty, S. Rinné, Aytuğ K. Kiper, Magdalena Platzk, Thomas Müller, et al. “5-(Indol-2-Yl)Pyrazolo[3,4-b]Pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis.” Molecules (2021).
MLA
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Ramírez, D., et al. “5-(Indol-2-Yl)Pyrazolo[3,4-b]Pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis.” Molecules, 2021.
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@article{d2021a,
title = {5-(Indol-2-yl)pyrazolo[3,4-b]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis},
year = {2021},
journal = {Molecules},
author = {Ramírez, D. and Mejia-Gutierrez, M. and Insuasty, B. and Rinné, S. and Kiper, Aytuğ K. and Platzk, Magdalena and Müller, Thomas and Decher, N. and Quiroga, J. and De-la-Torre, P. and González, W.}
}
Abstract
TASK channels belong to the two-pore-domain potassium (K2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors makes these bioactive compounds very appealing to explore new cancer and neurological therapies. TASK-3 channel blockers are very limited to date, and only a few heterofused compounds have been reported in the literature. In this article, we combined a pharmacophore hypothesis with molecular docking to address for the first time the rational design, synthesis, and evaluation of 5-(indol-2-yl)pyrazolo[3,4-b]pyridines as a novel family of human TASK-3 channel blockers. Representative compounds of the synthesized library were assessed against TASK-3 using Fluorometric imaging plate reader—Membrane Potential assay (FMP). Inhibitory properties were validated using two-electrode voltage-clamp (TEVC) methods. We identified one active hit compound (MM-3b) with our systematic pipeline, exhibiting an IC50 ≈ 30 μM. Molecular docking models suggest that compound MM-3b binds to TASK-3 at the bottom of the selectivity filter in the central cavity, similar to other described TASK-3 blockers such as A1899 and PK-THPP. Our in silico and experimental studies provide a new tool to predict and design novel TASK-3 channel blockers.