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

• Published in: European journal of medicinal chemistry Vol. 262; p. 115910
• Main Authors: Ishida, Ryosuke, Kurebayashi, Nagomi, Iinuma, Hiroto, Zeng, Xi, Mori, Shuichi, Kodama, Masami, Murayama, Takashi, Masuno, Hiroyuki, Takeda, Fumi, Kawahata, Masatoshi, Tanatani, Aya, Miura, Aya, Nishio, Hajime, Sakurai, Takashi, Kagechika, Hiroyuki
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.12.2023; Elsevier
• Subjects: Arrhythmias drug candidate; Ca2+ channel inhibitor; Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Ryanodine receptor 2; Science & Technology; Structure-activity relationship; Arrhythmias drug candidate; Ryanodine receptor 2; Ca2+ channel inhibitor; Structure-activity relationship; POLYMORPHIC VENTRICULAR-TACHYCARDIA; TETRAZOLES; DANTROLENE; MALIGNANT HYPERTHERMIA; CONVERSION; SARCOPLASMIC-RETICULUM; RELEASE CHANNEL; PHARMACOLOGY; Ca 2+channel inhibitor; MOUSE MODEL; MUTATIONS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115910

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. TMDJ-035 with cis-amide configuration could suppress abnormal Ca2+ signals in cardiomyocytes from RyR2-mutated mice. [Display omitted] •The novel RyR2 selective inhibitor 1 was identified.•Structure-activity relationship discovered quite potent RyR2 inhibitor TMDJ-035.•The amide conformation of TMDJ-035 was verified as cis-amide, which is crucial for the activity expression.•TMDJ-035 showed complete selectivity among RyRs.•TMDJ-035 could suppress the abnormal Ca2+ signals in cardiomyocytes from RyR2-mutated mice.