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

Wieting JM, Vadukoot AK, Sharma S, Abney KK, Bridges TM, Daniels JS, Morrison RD, Wickman K, Weaver CD, Hopkins CR
ACS Chem Neurosci. 2017 8 (9): 1873-1879

PMID: 28697302 · PMCID: PMC6116837 · DOI:10.1021/acschemneuro.7b00217

The G protein-gated inwardly-rectifying potassium channels (GIRK, K3) 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 > 0.6).

MeSH Terms (13)

Acetamides Animals Brain G Protein-Coupled Inwardly-Rectifying Potassium Channels HEK293 Cells Humans Liver Membrane Transport Modulators Mice Microsomes, Liver Molecular Structure Pyrazoles Structure-Activity Relationship

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