A potent and selective cis-amide inhibitor of ryanodine receptor 2 as a candidate for cardiac arrhythmia treatment

  • Eur J Med Chem. 2023 Dec 15:262:115910. doi: 10.1016/j.ejmech.2023.115910.
Ryosuke Ishida  1 ,  Nagomi Kurebayashi  2 ,  Hiroto Iinuma  1 ,  Xi Zeng  1 ,  Shuichi Mori  1 ,  Masami Kodama  3 ,  Takashi Murayama  3 ,  Hiroyuki Masuno  1 ,  Fumi Takeda  4 ,  Masatoshi Kawahata  5 ,  Aya Tanatani  4 ,  Aya Miura  6 ,  Hajime Nishio  6 ,  Takashi Sakurai  3 ,  Hiroyuki Kagechika  7
Affiliations
  • 1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, 101-0062, Japan.
  • 2. Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan. Electronic address: [email protected].
  • 3. Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.
  • 4. Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo, 112-8610, Japan.
  • 5. Faculty of Pharmaceutical Sciences, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan.
  • 6. Department of Legal Medicine, Hyogo Medical University, Nishinomiya, 663-8501, Japan.
  • 7. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, 101-0062, Japan. Electronic address: [email protected].
PMID: 37922828 DOI: 10.1016/j.ejmech.2023.115910
Abstract

Ryanodine receptor 2 (RyR2) is a CA2+ release channel mainly located on the sarcoplasmic reticulum (SR) membrane of heart muscle cells and regulates the concentration of CA2+ in the cytosol. RyR2 overactivation causes potentially lethal cardiac arrhythmias, but no specific inhibitor is yet available. Herein we developed the first highly potent and selective RyR2 inhibitor, TMDJ-035, containing 3,5-difluoro substituents on the A ring and a 4-fluoro substituent on the B ring, based on a comprehensive structure-activity relationship (SAR) study of tetrazole compound 1. The SAR study also showed that the amide conformation is critical for inhibitory potency. Single-crystal X-ray diffraction analysis and variable-temperature 1H NMR revealed that TMDJ-035 strongly favors cis-amide configuration, while the inactive analogue TMDJ-011 with a secondary amide takes trans-amide configuration. Examination of the selectivity among RyRs indicated that TMDJ-035 displayed high selectivity for RyR2. TMDJ-035 suppressed abnormal CA2+ waves and transients in isolated cardiomyocytes from RyR2-mutated mice. It appears to be a promising candidate drug for treating cardiac arrhythmias due to RyR2 overactivation, as well as a tool for studying the mechanism and dynamics of RyR2 channel gating.

Keywords
Arrhythmias drug candidate; Ca(2+) channel inhibitor; Ryanodine receptor 2; Structure-activity relationship.
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