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


Wieting JMJoshua M , Vadukoot AKAnish K , Sharma SSwagat , Abney KKKristopher K , Bridges TMThomas M , Daniels JSJ Scott , Morrison RDRyan D , Wickman KKevin , Weaver CDC David , Hopkins CRCorey R . ACS chemical neuroscience. 2017 07 19; 8(9). 1873-1879


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).