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
  • 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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