Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators

Joshua M. Wieting; Anish K. Vadukoot; Swagat Sharma; Kristopher K. Abney; Thomas M. Bridges; J. Scott Daniels; Ryan D. Morrison; Kevin Wickman; C. David Weaver; Corey R. Hopkins

doi:10.1021/acschemneuro.7b00217

Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators

Joshua M. Wieting, Anish K. Vadukoot, Swagat Sharma, Kristopher K. Abney, Thomas M. Bridges, J. Scott Daniels, Ryan D. Morrison, Kevin Wickman, C. David Weaver, Corey R. Hopkins

Pharmacology

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

13 Scopus citations

Abstract

The G protein-gated inwardly-rectifying potassium channels (GIRK, K_ir3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent K_p > 0.6).

Original language	English (US)
Pages (from-to)	1873-1879
Number of pages	7
Journal	ACS Chemical Neuroscience
Volume	8
Issue number	9
DOIs	https://doi.org/10.1021/acschemneuro.7b00217
State	Published - Sep 20 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

GIRK
K3
activator
pharmacokinetics
thallium flux

Publisher link

10.1021/acschemneuro.7b00217

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116837

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Wieting, J. M., Vadukoot, A. K., Sharma, S., Abney, K. K., Bridges, T. M., Daniels, J. S., Morrison, R. D., Wickman, K., Weaver, C. D., & Hopkins, C. R. (2017). Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators. ACS Chemical Neuroscience, 8(9), 1873-1879. https://doi.org/10.1021/acschemneuro.7b00217

Wieting, JM, Vadukoot, AK, Sharma, S, Abney, KK, Bridges, TM, Daniels, JS, Morrison, RD, Wickman, K, Weaver, CD & Hopkins, CR 2017, 'Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators', ACS Chemical Neuroscience, vol. 8, no. 9, pp. 1873-1879. https://doi.org/10.1021/acschemneuro.7b00217

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abstract = "The G protein-gated inwardly-rectifying potassium channels (GIRK, Kir3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent Kp > 0.6).",

keywords = "GIRK, K3, activator, pharmacokinetics, thallium flux",

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doi = "10.1021/acschemneuro.7b00217",

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AU - Sharma, Swagat

AU - Abney, Kristopher K.

AU - Bridges, Thomas M.

AU - Daniels, J. Scott

AU - Morrison, Ryan D.

AU - Wickman, Kevin

AU - Weaver, C. David

AU - Hopkins, Corey R.

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AB - The G protein-gated inwardly-rectifying potassium channels (GIRK, Kir3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent Kp > 0.6).

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KW - pharmacokinetics

KW - thallium flux

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Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators

Abstract

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Keywords

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