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 Ca release channel that controls the concentration of Ca 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.