Allosteric inhibitor of the KCNN4 channel for atrial fibrillation

An allosteric inhibitor of the KCNN4 potassium channel expressed in heart tissues could help treat atrial fibrillation by selectively blocking the channel's PIP2-calmodulin binding domain instead of the channel's pore, which is conserved in related channels.

Screening of a library of 45 2-benzimidazolinone analogs for the ability to inhibit KCNN4 currents in a hamster cell line, followed by optimization of the screen's top hit, identified a compound — comprising an abenzoxazole ring bearing a carbonyl group and a linear heptyl tail connected to the benzoxazole nitrogen — that inhibited KCNN4 currents with an IC50 of 8.6 μM...