|Chemical and physical data|
|Molar mass||401.43 g/mol|
|3D model (Jmol)|
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 myocardical 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. It also increases the rate of phosphate release from myosin, 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. The overall result of omecamtiv mecarbil is an increase in left ventricular systolic ejection time, sarcomere shortening and stroke volume, while the systolic pressure remains the same. This causes a decrease in heart rate while myocardial oxygen consumption is unaffected. The increased cardiac output is independent of intracellular calcium and cAMP levels. Thus omecamtiv mecarbil improves systolic function by increasing the systolic ejection duration/stroke volume, without consuming more ATP energy, oxygen or altering intracellular calcium levels causing an overall improvement in cardiac efficiency.
Experimental studies on rats and dogs, proved the efficacy and mechanism of action of omecamtiv mecarbil. Current clinical studies on humans have shown there is a direct linear relationship between dose and systolic ejection time. The dose-dependent effects persisted throughout the entire trial, suggesting that desensitization does not occur. The maximum tolerated dose was observed to be an infusion of 0.5 mg/kg/h. Adverse effects, such as ischemia, were only seen at doses beyond this level, due to extreme lengthening of systolic ejection time. Thus due to the unique cardiac myosin activation mechanism, omecamtiv mecarbil could safely improve cardiac function within tolerated doses. Omecamtiv mecarbil effectively relieves symptoms and enhances the quality of life of systolic heart failure patients. It drastically improves cardiac performance in the short term; however, the hopeful long-term effects of reduced mortality have yet to be studied.
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