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

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

  • ACS Chem Neurosci. 2017 Sep 20;8(9):1873-1879. doi: 10.1021/acschemneuro.7b00217.
Joshua M Wieting 1,  Anish K Vadukoot 2,  Swagat Sharma 2,  Kristopher K Abney 3,  Thomas M Bridges 1,  J Scott Daniels 4,  Ryan D Morrison 4,  Kevin Wickman 5,  C David Weaver 6 7,  Corey R Hopkins 2
Affiliations

Affiliations

  • 1 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University , Nashville, Tennessee 37232, United States.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
  • 3 Department of Neuroscience and Pharmacology, Meharry Medical College , Nashville, Tennessee 37208, United States.
  • 4 Sano Informed Prescribing , Franklin, Tennessee 37067, United States.
  • 5 Department of Pharmacology, University of Minnesota , Minneapolis, Minnesota 55455, United States.
  • 6 Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
  • 7 Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.
PMID: 28697302 DOI: 10.1021/acschemneuro.7b00217
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; Kir3; activator; pharmacokinetics; thallium flux.

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