Structure-activity optimization of ryanodine receptor modulators for the treatment of catecholaminergic polymorphic ventricular tachycardia.

IF 5.6 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Heart rhythm Pub Date : 2024-10-02 DOI:10.1016/j.hrthm.2024.09.062

Oliver M Moore, Martha Sibrian-Vazquez, Jose Alberto Navarro-Garcia, Yuriana Aguilar-Sanchez, Mara R Turkieltaub-Paredes, Satadru K Lahiri, Li Ni, Tarah A Word, Christina Y Miyake, Robert M Strongin, Xander H T Wehrens

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引用次数: 0

Abstract

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with lethal arrhythmias. Most CPVT cases are caused by inherited variants in the gene encoding ryanodine receptor type 2 (RYR2).

Objective: The goal of this study was to investigate the structure-activity relationship of tetracaine derivatives and to test a lead compound in a mouse model of CPVT.

Methods: We synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca²⁺ handling in cardiomyocytes from R176Q/+ mice was tested with confocal microscopy. The effects of lead compound MSV1302 on arrhythmia inducibility and cardiac contractility were tested by programmed electrical stimulation and echocardiography, respectively. Plasma and microsomal stability and cytotoxicity assays were also performed.

Results: Ca²⁺ imaging revealed that 3 of 11 compounds suppressed sarcoplasmic reticulum Ca²⁺ leak through mutant RyR2. Two compounds selected for further testing exhibited a half-maximal effective concentration of 146 nM (MSV1302) and 49 nM (MSV1406). Whereas neither compound altered baseline electrocardiogram intervals, only MSV1302 suppressed stress- and pacing-induced ventricular tachycardia in vivo in R176Q/+ mice. Echocardiography revealed that the lead compound MSV1302 did not negatively affect cardiac inotropy and chronotropy. Finally, compound MSV1302 did not block I_Na, I_Ca,L, or I_Kr; it exhibited excellent stability in plasma and microsomes, and it was not cytotoxic.

Conclusion: Structure-activity relationship studies of second-generation tetracaine derivatives identified lead compound MSV1302 with a favorable pharmacokinetic profile. MSV1302 normalized aberrant RyR2 activity in vitro and in vivo, without altering cardiac inotropy, chronotropy, or off-target effects on other ion channels. This compound may be a strong candidate for future clinical studies to determine its efficacy in CPVT patients.

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用于治疗儿茶酚胺能多态性室性心动过速的瑞诺丁受体调节剂的结构活性优化。

背景：儿茶酚胺能多态性室性心动过速（CPVT）是一种遗传性心律失常疾病，与潜在的致命性心律失常有关。大多数 CPVT 病例是由 2 型雷诺丁受体（RYR2）基因的遗传变异引起的：研究四卡因衍生物的结构活性关系，并在 CPVT 小鼠模型中测试一种先导化合物：我们合成了超过 200 种四卡因衍生物，并对其中 11 种进行了表征。使用共聚焦显微镜检测了这些化合物对 R176Q/+ 小鼠心肌细胞中 Ca2+ 处理的影响。利用程序电刺激和超声心动图分别测试了先导化合物 MSV1302 对心律失常诱导性和心脏收缩力的影响。此外，还进行了血浆和微粒体稳定性及细胞毒性检测：Ca2+ 成像显示，11 种化合物中有 4 种抑制了通过突变型 RyR2 的肌质网 Ca2+ 泄漏。两种被选作进一步测试的化合物的 EC50 分别为 146 nM（MSV1302）和 49 nM（MSV1406）。虽然这两种化合物都不会改变基线心电图间隔，但只有 MSV1302 能抑制 R176Q/+ 小鼠体内应激和起搏诱发的室性心动过速。超声心动图显示，先导化合物 MSV1302 不会对心脏收缩力和时速产生负面影响。最后，化合物 MSV1302 没有阻断 INa、ICa,L 或 IKr，在血浆和微粒体中表现出良好的稳定性，并且没有细胞毒性：第二代四卡因衍生物的结构活性关系研究发现了具有良好药代动力学特征的先导化合物 MSV1302。MSV1302 可使体外和体内异常的 RyR2 活性正常化，而不会改变心肌收缩力、心动过速或对其他离子通道的脱靶效应。该化合物可能是未来临床研究的有力候选药物，以确定其对 CPVT 患者的疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Heart rhythm 医学-心血管系统

CiteScore

10.50

自引率

5.50%

发文量

1465

审稿时长

24 days

期刊介绍： HeartRhythm, the official Journal of the Heart Rhythm Society and the Cardiac Electrophysiology Society, is a unique journal for fundamental discovery and clinical applicability. HeartRhythm integrates the entire cardiac electrophysiology (EP) community from basic and clinical academic researchers, private practitioners, engineers, allied professionals, industry, and trainees, all of whom are vital and interdependent members of our EP community. The Heart Rhythm Society is the international leader in science, education, and advocacy for cardiac arrhythmia professionals and patients, and the primary information resource on heart rhythm disorders. Its mission is to improve the care of patients by promoting research, education, and optimal health care policies and standards.