S107 hydrochloride是一种能够特异性结合RyR2、增强calstabin2结合并抑制RyR2通道Ca2+泄漏的小分子化合物，具有口服活性，能够穿透血脑屏障。
Cas No.:1357476-46-0
Sample solution is provided at 25 µL, 10mM.
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S107 hydrochloride is a small molecule compound that can specifically bind to RyR2, enhance calstabin2 binding, and inhibit Ca2+ leakage in RyR2 channels. S107 hydrochloride has oral activity and can penetrate the blood-brain barrier [1-2]. S107 hydrochloride can improve muscle function, prevent arrhythmia, and increase seizure threshold by stabilizing RyR FKBP complex, making it a promising candidate drug for the treatment of catechol polymorphic ventricular tachycardia (CPVT)[3-5].
In vitro, treatment of cardiomyocytes(carrying RyR2-I4587V mutation; CPVT-hiPSC-CMs) isolated from CPVT patients with 10μM S107 hydrochloride for 2-3h inhibited the frequency of DAD (Delayed Afterdepolarization) in cells in a concentration-dependent manner, producing an antiarrhythmic effect[3]. Treatment of Rbm20 KO rat cardiomyocytes with S107 hydrochloride (10μM) for 2-3h restored the damaged contractile properties of the cells to the level of WT cardiomyocytes, inhibited Ca2+ leakage, restored the intracellular Ca2+ level at rest, and alleviated the increase in ΔFFI caused by electrical stimulation[4].
In vivo, treatment of Ryr2-R2474S epilepsy model mice with an implantable osmotic pump and a dosage of 5mg/kg/h using S107 hydrochloride for 7 days can restore brain RyR channel activity to normal levels, repair mutated channel Ca2+ leakage, and prevent fatal arrhythmias[1]. S107 hydrochloride was administered to Huntington's disease model mice via drinking water at a dose of 75mg/kg/d for one month, preventing the dissociation of calstabin2 from cardiac RyR2, reducing endoplasmic reticulum Ca2+ leakage, and significantly improving motor coordination disorder and cognitive dysfunction[6]. Male arrhythmia mice with C57BL/10ScSc-Dmdmdx/J ingested S107 hydrochloride (25mg/100mL) daily in drinking water, which inhibited the depletion of calstabin1 in the RyR1 macromolecular complex in skeletal muscle, prevented the increase in the frequency of spontaneous SR Ca2+ release events, and alleviated the abnormal electrocardiogram and ventricular arrhythmia in mice[7].
References:
[1]. Lehnart S E, Mongillo M, Bellinger A, et al. Leaky Ca 2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice[J]. The Journal of clinical investigation, 2008, 118(6): 2230-2245.
[2]. Mei Y, Xu L, Kramer H H, et al. Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1, 4-benzothiazepine derivative S107[J]. Biophysical Journal, 2013, 104(2): 443a.
[3]. Sasaki K, Makiyama T, Yoshida Y, et al. Patient-specific human induced pluripotent stem cell model assessed with electrical pacing validates S107 as a potential therapeutic agent for catecholaminergic polymorphic ventricular tachycardia[J]. PLoS One, 2016, 11(10): e0164795.
[4]. Guo W, Zhu C, Yin Z, et al. The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes[J]. Physiological Reports, 2021, 9(17): e15011.
[5]. Popa M A. Effect of Experimental Drug S107 on Accessory Protein Binding to the RyR[J]. 2012.
[6]. Dridi H, Liu X, Yuan Q, et al. Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease[J]. JCI insight, 2020, 5(19): e140614.
[7]. Fauconnier J, Thireau J, Reiken S, et al. Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy[J]. Proceedings of the National Academy of Sciences, 2010, 107(4): 1559-1564.
S107 hydrochloride是一种能够特异性结合RyR2、增强calstabin2结合并抑制RyR2通道Ca2+泄漏的小分子化合物，具有口服活性，能够穿透血脑屏障[1-2]。S107 hydrochloride能够通过稳定RyR-FKBP复合物改善肌肉功能，预防心律失常，提高癫痫发作阈值，是治疗儿茶酚能多态性心室心动过速（CPVT）的有前景候选药物[3-5]。
在体外，用10μM S107 hydrochloride处理从CPVT患者中分离诱导的心肌细胞（携带RyR2-I4587V突变；CPVT-hiPSC-CMs）2-3h，以浓度依赖性方式抑制细胞中DAD（延迟后除极）的频率，产生抗心律失常效应[3]。S107 hydrochloride（10μM）处理Rbm20 KO大鼠心肌细胞2-3h能够将细胞受损的收缩性特性恢复到WT心肌细胞水平，抑制了Ca2+泄漏，恢复了静息细胞内Ca2+水平，缓解了电刺激引起的∆FFI升高[4]。
在体内，通过植入式渗透泵使用S107 hydrochloride (5mg/kg/h)处理Ryr2-R2474S癫痫模型小鼠7天能够恢复脑RyR通道活动至正常水平，修复突变通道Ca2+泄漏情况，预防致命的心律失常的发生[1]。S107 hydrochloride以75mg/kg/d的剂量饮用水给药亨廷顿舞蹈病模型小鼠一个月，防止了calstabin2与心脏RyR2的解离，减轻了内质网Ca-2+泄漏情况，显著改善了运动协调失调及认知功能障碍[6]。 C57BL/10ScSc-Dmdmdx/J雄性心律失常小鼠每日饮水摄入S107 hydrochloride（25mg/100mL），能够抑制骨骼肌中RyR1大分子复合物中calstabin1的耗竭，防止了自发性SR Ca2+释放事件发生频率的增加，缓解了小鼠心电图异常和心室性心律失常的情况[7]。
| Cell experiment [1]: | |
Cell lines | Rbm20 KO rat cardiomyocytes |
Preparation Method | Isolation of cardiomyocytes from 6-month-old Rbm20 KO rats. Cardiomycoytes were treated with 10µM of freshly prepared S107 hydrochloride and incubated for 2-3h at room temperature prior to the experiments and cardiomyocytes treated with vehicle were served as control. Using the SoftEdge Myocam system to record cell and sarcomere length, capturing changes in myocardial cell length during shortening and re lengthening, and detecting transient intracellular Ca2+ levels using Fura-2 AM (0.5μM). |
Reaction Conditions | 10μM; 2-3h |
Applications | The treatment with S107 hydrochloride was able to restore the contractile properties of damaged cells to the level of WT cardiomyocytes, inhibit Ca2+ leakage, restore resting intracellular Ca2+ levels, and alleviate the increase in ∆FFI caused by electrical stimulation. |
| Animal experiment [2]: | |
Animal models | Q175-Z heterozygous mice exhibiting pathological status of Huntington's disease |
Preparation Method | The S107 hydrochloride was administered in drinking water at for 1 month as previously described. Mouse brain tissue samples were taken for immunohistochemistry. Take a frozen diaphragm strip from the left middle segment of the mouse rib diaphragm to measure the cross-sectional area of the diaphragm fibers, and test the contractile function of the mouse diaphragm or soleus muscle samples. |
Dosage form | 75mg/kg/d; 1 month; p.o. |
Applications | S107 hydrochloride can prevent the dissociation of calstabin2 from the heart RyR2, reduce the leakage of Ca2+ from the endoplasmic reticulum, significantly improve motor coordination disorders and cognitive dysfunction, and restore diaphragmatic muscle strength in mice. |
References: | |
| Cas No. | 1357476-46-0 | SDF | |
| Canonical SMILES | COC1=CC=C2SCCN(CC2=C1)C.Cl | ||
| 分子式 | C11H16ClNOS | 分子量 | 245.77 |
| 溶解度 | 100mg/ml in DMSO | 储存条件 | Store at -20°C |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.0688 mL | 20.3442 mL | 40.6884 mL |
| 5 mM | 813.8 μL | 4.0688 mL | 8.1377 mL |
| 10 mM | 406.9 μL | 2.0344 mL | 4.0688 mL |
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| % DMSO % % Tween 80 % saline | ||||||||||
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