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Omecamtiv mecarbil | 奥美康地

Omecamtiv mecarbil (INN), previously referred to as CK-1827452, is a cardiac-specific myosin activator. It is being studied for a potential role in the treatment of left ventricular systolic heart failure.

Systolic heart failure involves a loss of effective actin-myosin cross bridges in the myocytes (heart muscle cells) of the left ventricle, which leads to a decreased ability of the heart to move blood through the body. This causes peripheral edema (blood pooling), which the sympathetic nervous system tries to correct by overstimulating the cardiac myocytes, leading to left ventricular hypertrophy, another characteristic of chronic heart failure.

Current inotropic therapies work by increasing the force of cardiac contraction, such as through calcium conduction or modulating adrenoreceptors. But these are limited by adverse events, including arrhythmias related to increased myocardial oxygen consumption, desensitization of adrenergic receptors, and altering intracellular calcium levels. Inotropes are also thought to be associated with worse prognosis. Therefore, the novel mechanism of omecamtiv mecarbil may offer a useful new option for heart failure.

Mechanism of action: Cardiac myocytes contract through a cross-bridge cycle between the myofilaments, actin and myosin. Chemical energy in the form of ATP is converted into mechanical energy which allows myosin to strongly bind to actin and produce a power stroke resulting in sarcomere shortening/contraction. Omecamtiv mecarbil specifically targets and activates myocardial ATPase and improves energy utilization. This enhances effective myosin cross-bridge formation and duration, while the velocity of contraction remains the same. Specifically, it increases the rate of phosphate release from myosin by stabilizing the pre-powerstroke and the phosphate release states, thereby accelerating the rate-determining step of the cross-bridge cycle, which is the transition of the actin-myosin complex from the weakly bound to the strongly bound state. Furthermore, once myosin is bound to actin, it stays bound dramatically longer in the presence of omecamtiv mecarbil. The combination of increased and prolonged cross-bridge formation prolongs myocardial contraction. Thus, the overall clinical result of omecamtiv mecarbil is an increase in left ventricular systolic ejection time and ejection fraction.

Omecamtiv mecarbi以前称为 CK-1827452,是一种心脏特异性肌球蛋白激活剂。正在研究它在治疗左心室收缩性心力衰竭中的潜在作用。收缩性心力衰竭涉及左心室肌细胞(心肌细胞)中有效的肌动蛋白-肌球蛋白交叉桥的丧失,这导致心脏将血液输送到全身的能力下降。这会导致外周水肿(血液淤积) / 左心室肥厚,这是慢性心力衰竭的另一个特征。 

当前的正性肌力疗法通过增加心脏收缩力起作用,例如通过钙传导或调节肾上腺素受体。但这些都受到不良事件的限制,包括与心肌耗氧量增加、肾上腺素受体脱敏和细胞内钙水平改变相关的心律失常。 正性肌力药也被认为与较差的预后有关。

 因此,omecamtiv mecarbil 的新机制可能为心力衰竭提供一个新选择。 Omecamtiv mecarbil 专门针对并激活心肌 ATP 酶并提高能量利用率。这增强了有效的肌球蛋白跨桥形成和持续时间,而收缩速度保持不变。 具体来说,它通过稳定前动力冲程和磷酸盐释放状态来增加肌球蛋白释放磷酸盐的速率,从而加速跨桥循环的速率决定步骤,即肌动蛋白-肌球蛋白复合物的转变从弱束缚态到强束缚态。 此外在 omecamtiv mecarbil 存在的情况下, 肌球蛋白与肌动蛋白的结合时间会显着延长。因此,omecamtiv mecarbil 的总体临床结果是增加左心室收缩期射血时间和射血分数 。

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