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

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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)1873-1879
Number of pages7
JournalACS Chemical Neuroscience
Volume8
Issue number9
DOIs
StatePublished - Sep 20 2017

Bibliographical note

Funding Information:
*Phone: 402-559-9729. Fax: 402-559-5643. E-mail: corey. hopkins@unmc.edu. ORCID Corey R. Hopkins: 0000-0003-4958-1697 Author Contributions C.R.H oversaw and designed the chemistry. J.M.W., A.K.V., and S.S. performed the synthetic chemistry work. T.M.B., J.S.D., and R.D.M. designed and performed the drug metabolism and pharmacokinetic in vitro experiments and in vivo studies. K.W. helped with the manuscript and in vivo studies. C.D.W. designed and analyzed the in vitro pharmacology experiments. K.K.A. performed and analyzed the in vitro pharmacology experiments. C.R.H. wrote the manuscript with input from all authors. Funding The work was supported by a NIH Grant 5R01MH107399 (C.R.H., C.D.W., and K.W.). Notes The authors declare the following competing financial interest(s): C.D.W. is the president of WaveFront Biosciences, the maker of the Panoptic kinetic imaging plate reader used to perform the in vitro pharmacology experiments. C.D.W.

Keywords

  • GIRK
  • K3
  • activator
  • pharmacokinetics
  • thallium flux

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