Development of selective RyR2 inhibitors with a pharmacophore containing a parabanic acid skeleton

Gene mutations resulting in dysfunction of the ryanodine receptor type 2 (RyR2), a huge Ca²⁺ release channel that controls the concentration of Ca²⁺ in the cytosol of cardiac muscle cells, can cause fatal heart arrhythmias. However, no RyR2 inhibitors have yet been developed for clinical usage. In this work, we discovered an isoform-selective RyR2 inhibitor 1 with a parabanic acid skeleton by screening a large chemical library. A detailed structure-activity relationship study of compound 1 showed that the parabanic acid skeleton was essential for inhibitory activity, and led to the development of the 15.5-fold more active inhibitor 18 through modifications at both side chains. Compound 18 selectively inhibited RyR2 among wild-type RyRs, and also inhibited RyR2 containing established pathogenic mutations, RyR2(R4495C) and RyR2(R2474S). These findings highlight the potential of the parabanic acid skeleton as a part of a pharmacophore for medicinal chemistry.