Omecamtiv mecarbil

Last updated
Omecamtiv mecarbil
Omecamtiv mecarbil.svg
Clinical data
Other namesCK-1827452
ATC code
  • None
Identifiers
  • Methyl 4-[(2-fluoro-3-{[N-(6-methylpyridin-3-yl)carbamoyl]amino}phenyl)methyl]piperazine-1-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C20H24FN5O3
Molar mass 401.442 g·mol−1
3D model (JSmol)
  • O=C(Nc1ccc(nc1)C)Nc2c(F)c(ccc2)CN3CCN(C(=O)OC)CC3
  • InChI=1S/C20H24FN5O3/c1-14-6-7-16(12-22-14)23-19(27)24-17-5-3-4-15(18(17)21)13-25-8-10-26(11-9-25)20(28)29-2/h3-7,12H,8-11,13H2,1-2H3,(H2,23,24,27)
  • Key:RFUBTTPMWSKEIW-UHFFFAOYSA-N

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. [1]

Contents

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 [2] 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. [3] Inotropes are also thought to be associated with worse prognosis. [4] Therefore, the novel mechanism of omecamtiv mecarbil has been proposed to be a potential 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. [5] 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. [6] Specifically, it increases the rate of phosphate release from myosin by stabilizing the pre-powerstroke and the phosphate release states, [7] 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. [8] [1] Furthermore, once myosin is bound to actin, it stays bound dramatically longer in the presence of omecamtiv mecarbil. [9] [10] [7] 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. [6] [8]

There is a slight decrease in heart rate while myocardial oxygen consumption is unaffected. The increased cardiac output is independent of intracellular calcium and cAMP levels. [3] [11] Thus omecamtiv mecarbil improves systolic function by increasing the systolic ejection duration and stroke volume, without consuming more ATP energy, oxygen or altering intracellular calcium levels causing an overall improvement in cardiac efficiency. [6]

Clinical trials

Experimental studies on rats and dogs, proved the efficacy and mechanism of action of omecamtiv mecarbil. [3] Current clinical studies on humans have shown there is a direct linear relationship between dose and systolic ejection time. [1] [12] [13] 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. [1] 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 improved cardiac performance in short-term studies; [1] [2] however, while the drug reduced the risk of hospitalization or other urgent care for heart failure by 8% in high-risk patients in the Phase III clinical trial GALACTIC-HF, patients receiving the drug did not live any longer. [14] The drug also did not improve exercise intolerance in heart failure patients in the Phase III METEORIC trial. [15] The METEORIC-HF randomized clinical trial found that omecamtiv mecarbil does not significantly improve exercise capacity. [16]

Myosin inhibition

Recently, research groups found that omecamtiv mecarbil actually inhibits myosin by enhancing the duty ratio, increasing calcium sensitivity and slowing force development. [17] It may still activate muscle as a whole however despite suppressing the working stroke of myosin. [18]

History

The U.S. Food and Drug Administration (FDA) granted in May 2020 a fast-track designation for omecamtiv mecarbil. The designation "represents an important milestone in the development of omecamtiv mecarbil," commented David Reese, head of R&D at Amgen, noting that "half of heart failure patients will die within five years of diagnosis, underscoring the urgent need for new therapies for this grievous condition". [19]

Related Research Articles

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A premature ventricular contraction (PVC) is a common event where the heartbeat is initiated by Purkinje fibers in the ventricles rather than by the sinoatrial node. PVCs may cause no symptoms or may be perceived as a "skipped beat" or felt as palpitations in the chest. PVCs do not usually pose any danger.

Systole is the part of the cardiac cycle during which some chambers of the heart contract after refilling with blood.

<span class="mw-page-title-main">Cardiac muscle</span> Muscular tissue of heart in vertebrates

Cardiac muscle is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of the heart. The cardiac muscle (myocardium) forms a thick middle layer between the outer layer of the heart wall and the inner layer, with blood supplied via the coronary circulation. It is composed of individual cardiac muscle cells joined by intercalated discs, and encased by collagen fibers and other substances that form the extracellular matrix.

<span class="mw-page-title-main">Troponin</span> Protein complex

Troponin, or the troponin complex, is a complex of three regulatory proteins that are integral to muscle contraction in skeletal muscle and cardiac muscle, but not smooth muscle. Measurements of cardiac-specific troponins I and T are extensively used as diagnostic and prognostic indicators in the management of myocardial infarction and acute coronary syndrome. Blood troponin levels may be used as a diagnostic marker for stroke or other myocardial injury that is ongoing, although the sensitivity of this measurement is low.

<span class="mw-page-title-main">Frank–Starling law</span> Relationship between stroke volume and end diastolic volume

The Frank–Starling law of the heart represents the relationship between stroke volume and end diastolic volume. The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles, before contraction, when all other factors remain constant. As a larger volume of blood flows into the ventricle, the blood stretches cardiac muscle, leading to an increase in the force of contraction. The Frank-Starling mechanism allows the cardiac output to be synchronized with the venous return, arterial blood supply and humoral length, without depending upon external regulation to make alterations. The physiological importance of the mechanism lies mainly in maintaining left and right ventricular output equality.

An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

<span class="mw-page-title-main">Muscle contraction</span> Activation of tension-generating sites in muscle

Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding something heavy in the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.

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<span class="mw-page-title-main">MYL2</span> Protein-coding gene in the species Homo sapiens

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene. This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).

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References

  1. 1 2 3 4 5 Teerlink JR (December 2009). "A novel approach to improve cardiac performance: cardiac myosin activators". Heart Failure Reviews. 14 (4): 289–298. doi:10.1007/s10741-009-9135-0. PMC   2772957 . PMID   19234787.
  2. 1 2 Dyke D, Koelling T (2008). "Heart failure due to left ventricular systolic dysfunction". In Eagle KA, Baliga RR (eds.). Practical Cardiology. Philadelphia: Lippincott Williams & Wilkins. pp. 246–285. ISBN   978-0-7817-7294-5.
  3. 1 2 3 Shen YT, Malik FI, Zhao X, Depre C, Dhar SK, Abarzúa P, et al. (July 2010). "Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure". Circulation. Heart Failure. 3 (4): 522–527. doi: 10.1161/CIRCHEARTFAILURE.109.930321 . PMID   20498236.
  4. ↑ Nieminen M (March 2005). "Pharmacological options for acute heart failure syndromes: current treatments and unmet needs". Eur Heart J. 7: B20-4. doi: 10.1093/eurheartj/sui009 .
  5. ↑ Bers DM (January 2002). "Cardiac excitation-contraction coupling". Nature. 415 (6868): 198–205. Bibcode:2002Natur.415..198B. doi:10.1038/415198a. PMID   11805843. S2CID   4337201.
  6. 1 2 3 Malik F, Teerlink J, Escandon R, Clake C, Wolff A (2006). "The Selective Cardiac Myosin Activator, CK-1827452, a Calcium-Independent Inotrope, Increases Left Ventricular Systolic Function by Increasing Ejection Time Rather than the Velocity of Contraction". Circulation. 114 (18 Suppl): 441.
  7. 1 2 Planelles-Herrero VJ, Hartman JJ, Robert-Paganin J, Malik FI, Houdusse A (August 2017). "Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil". Nature Communications. 8 (1): 190. Bibcode:2017NatCo...8..190P. doi:10.1038/s41467-017-00176-5. PMC   5543065 . PMID   28775348.
  8. 1 2 Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, et al. (March 2011). "Cardiac myosin activation: a potential therapeutic approach for systolic heart failure". Science. 331 (6023): 1439–1443. Bibcode:2011Sci...331.1439M. doi:10.1126/science.1200113. PMC   4090309 . PMID   21415352.
  9. ↑ Liu C, Kawana M, Song D, Ruppel KM, Spudich JA (June 2018). "Controlling load-dependent kinetics of β-cardiac myosin at the single-molecule level". Nature Structural & Molecular Biology. 25 (6): 505–514. doi:10.1038/s41594-018-0069-x. PMC   6092189 . PMID   29867217.
  10. ↑ Woody MS, Greenberg MJ, Barua B, Winkelmann DA, Goldman YE, Ostap EM (September 2018). "Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke". Nature Communications. 9 (1): 3838. doi: 10.1101/298141 . PMC   6155018 . PMID   30242219.
  11. ↑ Teerlink JR, Metra M, Zacà V, Sabbah HN, Cotter G, Gheorghiade M, Cas LD (December 2009). "Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond". Heart Failure Reviews. 14 (4): 243–253. doi:10.1007/s10741-009-9153-y. PMC   2772951 . PMID   19876734.
  12. ↑ Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM, Escandon RD, et al. (August 2011). "Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study". Lancet. 378 (9792): 667–675. doi:10.1016/S0140-6736(11)61219-1. PMID   21856480. S2CID   13366846.
  13. ↑ Cleland JG, Teerlink JR, Senior R, Nifontov EM, Mc Murray JJ, Lang CC, et al. (August 2011). "The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial". Lancet. 378 (9792): 676–683. doi:10.1016/S0140-6736(11)61126-4. PMID   21856481. S2CID   9411257.
  14. ↑ Mast J (October 9, 2020). "R&D Amgen's big cardiovascular bet with Cytokinetics hits PhIII primary but dramatically disappoints investors". Endpoints News. Retrieved 16 February 2022.
  15. ↑ Carroll J (February 15, 2022). "Cytokinetics' latest PhIII study of omecamtiv flops — kicking out another leg from under the market case it was building". Endpoints News. Retrieved 16 February 2022.
  16. ↑ Lewis GD, Voors AA, Cohen-Solal A, Metra M, Whellan DJ, Ezekowitz JA, et al. (July 2022). "Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial". JAMA. 328 (3): 259–269. doi:10.1001/jama.2022.11016. PMC   9297119 . PMID   35852527. S2CID   250642747.
  17. ↑ Swenson AM, Tang W, Blair CA, Fetrow CM, Unrath WC, Previs MJ, et al. (March 2017). "Omecamtiv Mecarbil Enhances the Duty Ratio of Human β-Cardiac Myosin Resulting in Increased Calcium Sensitivity and Slowed Force Development in Cardiac Muscle". The Journal of Biological Chemistry. 292 (9): 3768–3778. doi: 10.1074/jbc.M116.748780 . PMC   5339759 . PMID   28082673.
  18. ↑ Woody MS, Greenberg MJ, Barua B, Winkelmann DA, Goldman YE, Ostap EM (September 2018). "Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke". Nature Communications. 9 (1): 3838. Bibcode:2018NatCo...9.3838W. doi:10.1038/s41467-018-06193-2. PMC   6155018 . PMID   30242219.
  19. ↑ "FDA Grants Fast Track Designation For Omecamtiv Mecarbil In Heart Failure" (Press release). AMGEN. May 8, 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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