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

Abstract

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.

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

Supplementary files

Transparent peer review

To support increased transparency, we offer authors the option to publish the peer review history alongside their article.

View this article’s peer review history

Article information

Article type
Research Article
Submitted
27 Feb 2025
Accepted
06 Apr 2025
First published
10 Apr 2025

RSC Med. Chem., 2025, Advance Article

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

R. Ishida, X. Zeng, N. Kurebayashi, T. Murayama, S. Mori, Y. Yamamoto and H. Kagechika, RSC Med. Chem., 2025, Advance Article , DOI: 10.1039/D5MD00183H

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements