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

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posted on 11.07.2017 by 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
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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