The G protein regulated inwardly rectifying potassium channels (GIRK, Kir3) are a family of inward-rectifying potassium channels and are key effectors in signaling pathways. Four GIRK channel subunits are expressed, either as homo- or heterodimers in mammals: GIRK1, GIRK2, GIRK3 and GIRK4 and are expressed in both the CNS and the periphery. There is significant evidence supporting the roles of GIRK in a number of physiological processes and potential target for numerous indications, such as pain, epilepsy, reward/addiction and anxiety. Previously, our laboratory has identified a series of urea containing molecules as GIRK1/2 preferring activators. Unfortunately, the urea series suffers from significant PK liabilities (solubility, brain penetration) and due to these short-comings, we have identified a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This poster will detail our efforts in the identification, structure-activity relationship (SAR) and the in vitro and in vivo pharmacokinetic profiling of this new series of compounds.

Discovery and characterization of 1H-pyrazol-5-yl-2-phenylacetamides as novel, non-urea containing GIRK1/2 potassium channel activators

254th National Meeting (2017)

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