Mavacamten improves symptoms in obstructive hypertrophic cardiomyopathy patients.
Mavacamten improves symptoms in obstructive hypertrophic cardiomyopathy patients.
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Mavacamten 可改善梗阻性肥厚性心肌病患者的症状。
DOI：
10.1016/j.tips.2023.02.005
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发表时间：
2023
影响因子：
13.8
通讯作者：
Schlessinger,Avner
中科院分区：
文献类型：
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作者：
Zatorski,Nicole;Sobie,EricA;Schlessinger,Avner
结构：Mavacamten，3-(1-甲乙基)-6-[[(1S)-1-苯乙基]氨基]-2，4(1H，3H)-嘧啶二酮，是一种可逆的小分子心肌肌球蛋白ATPase变构抑制剂，分子式为C15H19N3O2，相对分子质量为273.33 g/m ol。它属于嘧啶二酮类药物。作用机制：梗阻性肥厚型心肌病患者的心壁较厚，主要在左心室。这是由于心肌细胞和肌原纤维紊乱以及心肌细胞过度生长(A)，这可能是遗传性的，也可能是由淀粉样变性等浸润性疾病造成的。心脏组织的结构变化影响肌动蛋白-肌球蛋白的跨桥，它负责心脏收缩，从而导致血液在全身的分布。在梗阻性肥厚型心肌病中，这些肌动蛋白-肌球蛋白交叉桥过多，导致左室流出道(LVOT)阻塞和心脏充盈受损，患者体验到胸痛、呼吸急促、晕厥和疲劳。ATP转化为ADP为肌动蛋白-肌球蛋白交叉桥的形成提供了所需的能量。Mavacamten可逆地与心肌肌球蛋白ATPase上的变构位点结合，抑制肌球蛋白结合的ATP的水解性。这限制了可用于结合肌动蛋白的肌球蛋白头部的数量，从而减少了收缩(产生力量的交叉桥)和舒张期(剩余交叉桥)的肌球蛋白跨桥形成(B)。通过减少交叉桥的数量，Mavacamten使LVOT压力和心脏充盈正常化，从而改善功能容量并减轻症状。
STRUCTURE: Mavacamten, 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl] amino]-2, 4 (1H, 3H)-pyrimidinedione, is a reversible small molecule allosteric inhibitor of cardiac myosin ATPase with a molecular formula of C15H19N3O2 and molecular weight of 273.33 g/mol. It belongs to the pyrimidinedione drug class. MECHANISM OF ACTION: The cardiac walls of patients with obstructive hypertrophic cardiomyopathy are thicker, primarily in the left ventricle. This is due to myocyte and myofibrillar disarray and excessive cardiac cell growth (A), which can be genetic or result from infiltrative disease such as amyloidosis. The structural changes to heart tissue affect actin-myosin cross-bridges, which are responsible for cardiac contraction and therefore blood distribution throughout the body. An overabundance of these actin-myosin cross-bridges, as seen in obstructive hypertrophic cardiomyopathy, results in Left Ventricular Outflow Tract (LVOT) obstruction and impaired cardiac filling, which patients experience as chest pain, shortness of breath, syncope, and fatigue. Conversion of ATP to ADP provides the energy necessary for actin-myosin cross-bridges formation. Mavacamten reversibly binds to an allosteric site on cardiac myosin ATPase, inhibiting the hydrolysis of myosin bound ATP. This limits the number of myosin heads that are available to bind actin, which then reduces actin-myosin cross-bridge formation in both systole (force-producing cross-bridges) and diastole (residual cross-bridges)(B). By decreasing the number of cross-bridges, Mavacamten normalizes LVOT pressure and cardiac filling, thereby ameliorating functional capacity and reducing symptoms.