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Omecamtiv mecarbil

Omecamtiv mecarbil
Clinical data
Other namesCK-1827452
ATC code
Identifiers
  • Methyl 4-[(2-fluoro-3-{[N-(6-methylpyridin-3-yl)carbamoyl]amino}phenyl)methyl]piperazine-1-carboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H24FN5O3
Molar mass401.442 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[1]), previously referred to as CK-1827452, is a cardiac-specific myosin activator. It is an experimental drug being studied for a potential role in the treatment of left ventricular systolic heart failure.[2]

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[3] by overstimulating the cardiac myocytes, leading to left ventricular hypertrophy, another characteristic of chronic heart failure.

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.[4] Inotropes are also thought to be associated with worse prognosis.[5]

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.[6] 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.[7] Specifically, it increases the rate of phosphate release from myosin by stabilizing the pre-powerstroke and the phosphate release states,[8] 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.[9][2] Furthermore, once myosin is bound to actin, it stays bound dramatically longer in the presence of omecamtiv mecarbil.[10][11][8] 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.[7][9]

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.[4][12] 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.[7]

Clinical trials

Experimental studies on rats and dogs, proved the efficacy and mechanism of action of omecamtiv mecarbil.[4] Clinical studies on humans have shown there is a direct linear relationship between dose and systolic ejection time.[2][13][14] 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.[2]

Omecamtiv mecarbil effectively relieves symptoms and enhances the quality of life of systolic heart failure patients. It improved cardiac performance in short-term studies;[2][3] 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.[15] The drug also did not improve exercise intolerance in heart failure patients in the Phase III METEORIC trial.[16] The METEORIC-HF randomized clinical trial found that omecamtiv mecarbil does not significantly improve exercise capacity.[17]

Myosin inhibition

Research groups found that omecamtiv mecarbil actually inhibits myosin by enhancing the duty ratio, increasing calcium sensitivity and slowing force development.[18] It may still activate muscle as a whole however despite suppressing the working stroke of myosin.[19]

History

The US Food and Drug Administration (FDA) granted, in May 2020, a fast-track designation for omecamtiv mecarbil.[20]

References

  1. ^ World Health Organization (2010). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 64". WHO Drug Information. 24 (3). hdl:10665/74577.
  2. ^ a b c d e 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.
  3. ^ a b 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.
  4. ^ a b c 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ a b c 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.
  8. ^ a b 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.
  9. ^ a b 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ Teerlink JR, Metra M, Zacà V, Sabbah HN, Cotter G, Gheorghiade M, et al. (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.
  13. ^ 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.
  14. ^ 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.
  15. ^ Mast J (9 October 2020). "R&D Amgen's big cardiovascular bet with Cytokinetics hits PhIII primary but dramatically disappoints investors". Endpoints News. Archived from the original on 16 February 2022. Retrieved 16 February 2022.
  16. ^ Carroll J (15 February 2022). "Cytokinetics' latest PhIII study of omecamtiv flops — kicking out another leg from under the market case it was building". Endpoints News. Archived from the original on 15 February 2022. Retrieved 16 February 2022.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ "FDA Grants Fast Track Designation For Omecamtiv Mecarbil In Heart Failure" (Press release). Amgen. 8 May 2020. Archived from the original on 22 April 2024. Retrieved 11 May 2020.

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