Further Structure-Activity Relationship of G Protein-Gated Inwardly Rectifying Potassium Channels 1/2 Activators: Synthesis and Biological Characterization of In Vitro Tool Compounds.

The work presented herein outlines the ongoing structure-activity relationship studies centered around a potent, efficacious, and selective activators of the G protein-gated inwardly rectifying potassium channels (GIRK)1/2 channel. Optimization studies centered around the pyrazole privileged scaffold, the N-1-position of the pyrazole, and the right-hand ether. The work confirms the necessity of the pyrazole, and a more potent GIRK1/2 activator is identified with ≈12-fold selectivity against GIRK1/4. The metabolite ID study is reported which shows the instability of the amide bond as the major site of metabolism (nonNADPH mediated). This work discovers another highly potent and selective GIRK1/2 activator for use as an in vitro tool compound.