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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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journal contribution
posted on 11.07.2017, 00:00 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).