Further SAR of GIRK1/2 positive allosteric modulators: Synthesis and Biological Characterization of In Vitro Tool Compounds

The work presented herein outlines the ongoing structure-activity relationship (SAR) studies centered around a potent, efficacious, and selective positive allosteric modulators (PAM) of the GIRK1/2 channel. Optimization studies centered around the pyrazole privileged scaffold, the N-1-position of the pyrazole and the right-hand ether. The work confirmed the necessity of the pyrazole, and we have identified a more potent GIRK1/2 activator with ~12-fold selectivity against GIRK1/4. We also report the metabolite ID study which shows the instability of the amide bond as the major site of metabolism (non-NADPH mediated). This work discovered another highly potent and selective GIRK1/2 activator for use as an in vitro tool compound.