295:
31:
1996:
529:
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.
558:
Omecamtiv mecarbil effectively relieves symptoms and enhances the quality of life of systolic heart failure patients. It improved cardiac performance in short-term studies; however, while the drug reduced the risk of hospitalization or other urgent care for heart failure by 8% in high-risk patients
549:
Experimental studies on rats and dogs, proved the efficacy and mechanism of action of omecamtiv mecarbil. 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
528:
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
1210:
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".
536:
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 and stroke volume, without consuming more ATP energy,
579:
Research groups found that omecamtiv mecarbil actually inhibits myosin by enhancing the duty ratio, increasing calcium sensitivity and slowing force development. It may still activate muscle as a whole however despite suppressing the working stroke of myosin.
1166:
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".
554:
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.
1618:
1294:
1489:
1263:
868:"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"
1611:
524:
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
1604:
462:(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
51:
1558:
Teerlink JR, Diaz R, Felker GM, McMurray JJ, Metra M, Solomon SD, et al. (January 2021). "Cardiac Myosin
Activation with Omecamtiv Mecarbil in Systolic Heart Failure".
1286:
2016:
1481:
1375:"Omecamtiv Mecarbil Enhances the Duty Ratio of Human β-Cardiac Myosin Resulting in Increased Calcium Sensitivity and Slowed Force Development in Cardiac Muscle"
1255:
371:
385:
1318:"Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial"
413:
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)
1950:
715:
432:
405:
84:
867:
1287:"Cytokinetics' latest PhIII study of omecamtiv flops — kicking out another leg from under the market case it was building"
1986:
706:
Dyke D, Koelling T (2008). "Heart failure due to left ventricular systolic dysfunction". In Eagle KA, Baliga RR (eds.).
589:
186:
2021:
1967:
1867:
1763:
274:
1119:"Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond"
1256:"R&D Amgen's big cardiovascular bet with Cytokinetics hits PhIII primary but dramatically disappoints investors"
551:
463:
613:
568:
480:
therapies work by increasing the force of cardiac contraction, such as through calcium conduction or modulating
560:
1426:"Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke"
1060:"Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke"
738:"Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure"
1955:
616:(2010). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 64".
467:
1742:
894:"Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil"
593:
235:
1596:
471:
1437:
1071:
965:
905:
819:
564:
290:
489:
101:
1655:
1355:
1236:
1192:
843:
563:
GALACTIC-HF, patients receiving the drug did not live any longer. The drug also did not improve
1316:
Lewis GD, Voors AA, Cohen-Solal A, Metra M, Whellan DJ, Ezekowitz JA, et al. (July 2022).
1117:
Teerlink JR, Metra M, Zacà V, Sabbah HN, Cotter G, Gheorghiade M, et al. (December 2009).
779:"Pharmacological options for acute heart failure syndromes: current treatments and unmet needs"
541:
or altering intracellular calcium levels causing an overall improvement in cardiac efficiency.
256:
1627:
1585:
1546:
1463:
1406:
1347:
1228:
1184:
1148:
1099:
1040:
991:
931:
835:
759:
711:
685:
513:
444:
246:
175:
1916:
1777:
1575:
1567:
1536:
1528:
1453:
1445:
1396:
1386:
1337:
1329:
1220:
1176:
1138:
1130:
1089:
1079:
1030:
1022:
981:
973:
921:
913:
827:
790:
749:
675:
667:
625:
485:
311:
110:
952:
Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, et al. (March 2011).
195:
2000:
509:
1373:
Swenson AM, Tang W, Blair CA, Fetrow CM, Unrath WC, Previs MJ, et al. (March 2017).
520:
shortening/contraction. Omecamtiv mecarbil specifically targets and activates myocardial
294:
1441:
1075:
969:
954:"Cardiac myosin activation: a potential therapeutic approach for systolic heart failure"
909:
892:
Planelles-Herrero VJ, Hartman JJ, Robert-Paganin J, Malik FI, Houdusse A (August 2017).
823:
754:
737:
1961:
1871:
1541:
1516:
1458:
1425:
1424:
Woody MS, Greenberg MJ, Barua B, Winkelmann DA, Goldman YE, Ostap EM (September 2018).
1401:
1342:
1317:
1143:
1118:
1094:
1058:
Woody MS, Greenberg MJ, Barua B, Winkelmann DA, Goldman YE, Ostap EM (September 2018).
1035:
1010:
986:
953:
926:
893:
680:
655:
481:
477:
1224:
1180:
1011:"Controlling load-dependent kinetics of β-cardiac myosin at the single-molecule level"
516:
which allows myosin to strongly bind to actin and produce a power stroke resulting in
2010:
1853:
1848:
1695:
1359:
448:
135:
1196:
1921:
1721:
1685:
1645:
1631:
1240:
847:
64:
59:
22:
1517:"Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil"
30:
736:
Shen YT, Malik FI, Zhao X, Depre C, Dhar SK, Abarzúa P, et al. (July 2010).
1900:
1885:
1838:
1752:
1726:
1675:
1670:
1640:
571:
found that omecamtiv mecarbil does not significantly improve exercise capacity.
505:
1449:
1084:
1059:
917:
795:
778:
1931:
1817:
1807:
1785:
1758:
1716:
1711:
1690:
1134:
1026:
671:
533:
347:
166:
1936:
1895:
1890:
1843:
1833:
1812:
1747:
1680:
1391:
1374:
1333:
977:
656:"A novel approach to improve cardiac performance: cardiac myosin activators"
525:
517:
1589:
1550:
1482:"FDA Grants Fast Track Designation For Omecamtiv Mecarbil In Heart Failure"
1467:
1410:
1351:
1232:
1188:
1152:
1103:
1044:
995:
935:
839:
763:
689:
567:
in heart failure patients in the Phase III METEORIC trial. The METEORIC-HF
1571:
496:
levels. Inotropes are also thought to be associated with worse prognosis.
466:
tries to correct by overstimulating the cardiac myocytes, leading to left
1880:
1801:
146:
447:
being studied for a potential role in the treatment of left ventricular
155:
1532:
630:
493:
488:
related to increased myocardial oxygen consumption, desensitization of
459:
121:
1580:
710:. Philadelphia: Lippincott Williams & Wilkins. pp. 246–285.
538:
521:
440:
226:
831:
810:
Bers DM (January 2002). "Cardiac excitation-contraction coupling".
504:
Cardiac myocytes contract through a cross-bridge cycle between the
215:
1485:
455:
370:
361:
262:
206:
1600:
1009:
Liu C, Kawana M, Song D, Ruppel KM, Spudich JA (June 2018).
279:
866:
Malik F, Teerlink J, Escandon R, Clake C, Wolff A (2006).
887:
885:
1984:
484:. But these are limited by adverse events, including
92:
Methyl 4-amino}phenyl)methyl]piperazine-1-carboxylate
454:
Systolic heart failure involves a loss of effective
1909:
1866:
1826:
1794:
1776:
1735:
1704:
1663:
1654:
1639:
359:
346:
310:
305:
273:
245:
225:
205:
185:
165:
145:
120:
100:
75:
50:
42:
37:
393:O=C(Nc1ccc(nc1)C)Nc2c(F)c(ccc2)CN3CCN(C(=O)OC)CC3
134:
109:
701:
699:
649:
647:
645:
643:
641:
1612:
8:
21:
947:
945:
1660:
1651:
1619:
1605:
1597:
731:
729:
727:
293:
174:
29:
2017:Drugs acting on the cardiovascular system
1579:
1540:
1457:
1400:
1390:
1341:
1142:
1093:
1083:
1034:
1015:Nature Structural & Molecular Biology
985:
925:
794:
753:
679:
629:
194:
1991:
861:
859:
857:
605:
410:
390:
289:
154:
89:
20:
1297:from the original on 15 February 2022
1266:from the original on 16 February 2022
512:in the form of ATP is converted into
255:
234:
7:
261:
63:
1560:The New England Journal of Medicine
1379:The Journal of Biological Chemistry
755:10.1161/CIRCHEARTFAILURE.109.930321
214:
125:
1492:from the original on 22 April 2024
14:
1515:Kaplinsky E, Mallarkey G (2018).
1994:
331:
328:
322:
418:Key:RFUBTTPMWSKEIW-UHFFFAOYSA-N
1630:excluding cardiac glycosides (
1285:Carroll J (15 February 2022).
592:(FDA) granted, in May 2020, a
532:There is a slight decrease in
337:
316:
1:
1225:10.1016/S0140-6736(11)61126-4
1181:10.1016/S0140-6736(11)61219-1
654:Teerlink JR (December 2009).
492:, and altering intracellular
458:-myosin cross bridges in the
435:), previously referred to as
1868:Phosphodiesterase inhibitors
590:Food and Drug Administration
470:, another characteristic of
2038:
1450:10.1038/s41467-018-06193-2
1085:10.1038/s41467-018-06193-2
918:10.1038/s41467-017-00176-5
742:Circulation: Heart Failure
464:sympathetic nervous system
306:Chemical and physical data
1945:
1254:Mast J (9 October 2020).
1135:10.1007/s10741-009-9153-y
1027:10.1038/s41594-018-0069-x
777:Nieminen M (March 2005).
672:10.1007/s10741-009-9135-0
614:World Health Organization
569:randomized clinical trial
401:
381:
80:
28:
1910:Other cardiac stimulants
796:10.1093/eurheartj/sui009
596:for omecamtiv mecarbil.
561:Phase III clinical trial
439:, is a cardiac-specific
1392:10.1074/jbc.M116.748780
1334:10.1001/jama.2022.11016
978:10.1126/science.1200113
468:ventricular hypertrophy
1743:Amezinium metilsulfate
594:fast-track designation
449:systolic heart failure
1572:10.1056/NEJMoa2025797
1430:Nature Communications
1123:Heart Failure Reviews
1064:Nature Communications
898:Nature Communications
660:Heart Failure Reviews
472:chronic heart failure
708:Practical Cardiology
618:WHO Drug Information
565:exercise intolerance
508:, actin and myosin.
490:adrenergic receptors
443:activator. It is an
1656:Adrenergic agonists
1442:2018NatCo...9.3838W
1076:2018NatCo...9.3838W
970:2011Sci...331.1439M
964:(6023): 1439–1443.
910:2017NatCo...8..190P
824:2002Natur.415..198B
500:Mechanism of action
25:
2022:Experimental drugs
1972:Never to phase III
1927:Omecamtiv mecarbil
1628:Cardiac stimulants
1533:10.7573/dic.212518
429:Omecamtiv mecarbil
23:Omecamtiv mecarbil
1982:
1981:
1862:
1861:
1827:Unknown/ungrouped
1778:Dopamine agonists
1772:
1771:
1484:(Press release).
1219:(9792): 676–683.
1175:(9792): 667–675.
818:(6868): 198–205.
717:978-0-7817-7294-5
575:Myosin inhibition
514:mechanical energy
445:experimental drug
426:
425:
372:Interactive image
275:CompTox Dashboard
16:Chemical compound
2029:
1999:
1998:
1997:
1990:
1917:Angiotensinamide
1661:
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1614:
1607:
1598:
1593:
1583:
1554:
1544:
1521:Drugs in Context
1502:
1501:
1499:
1497:
1478:
1472:
1471:
1461:
1421:
1415:
1414:
1404:
1394:
1385:(9): 3768–3778.
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1304:
1302:
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1038:
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878:(18 Suppl): 441.
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851:
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801:
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774:
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733:
722:
721:
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33:
26:
24:
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2007:
2006:
2005:
1995:
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1962:Clinical trials
1941:
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1509:Further reading
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1003:
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891:
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865:
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832:10.1038/415198a
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552:desensitization
547:
545:Clinical trials
510:Chemical energy
502:
482:adrenoreceptors
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1764:Norepinephrine
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1609:
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1595:
1594:
1566:(2): 105–116.
1555:
1510:
1507:
1504:
1503:
1488:. 8 May 2020.
1473:
1416:
1365:
1328:(3): 259–269.
1308:
1291:Endpoints News
1277:
1260:Endpoints News
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1202:
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1129:(4): 243–253.
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1021:(6): 505–514.
1001:
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769:
748:(4): 522–527.
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666:(4): 289–298.
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1854:Theodrenaline
1852:
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1849:Mephentermine
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1696:Phenylephrine
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263:RCSB PDB
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236:ChEMBL1800955
233:
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38:Clinical data
36:
32:
27:
19:
1926:
1922:Levosimendan
1722:Isoprenaline
1686:Norfenefrine
1646:dopaminergic
1563:
1559:
1524:
1520:
1494:. Retrieved
1476:
1433:
1429:
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1382:
1378:
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1299:. Retrieved
1290:
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531:
506:myofilaments
503:
476:
453:
436:
428:
427:
18:
1958:from market
1901:Vesnarinone
1886:Bucladesine
1839:Dimetofrine
1753:Epinephrine
1727:Prenalterol
1676:Methoxamine
1671:Metaraminol
1436:(1): 3838.
1301:16 February
1270:16 February
1070:(1): 3838.
872:Circulation
783:Eur Heart J
631:10665/74577
486:arrhythmias
355: g·mol
111:873697-71-3
76:Identifiers
43:Other names
2011:Categories
1932:Pimobendan
1818:Octopamine
1808:Dopexamine
1786:Fenoldopam
1759:Etilefrine
1717:Dobutamine
1712:Arbutamine
1641:Adrenergic
1581:2183/27253
1527:: 212518.
904:(1): 190.
600:References
534:heart rate
437:CK-1827452
360:3D model (
348:Molar mass
247:PDB ligand
196:2M19539ERK
167:ChemSpider
102:CAS Number
85:IUPAC name
46:CK-1827452
1968:Phase III
1956:Withdrawn
1937:Xamoterol
1896:Milrinone
1891:Enoximone
1844:Gepefrine
1834:Cafedrine
1813:Ibopamine
1748:Droxidopa
1681:Midodrine
1360:250642747
789:: B20-4.
526:phosphate
518:sarcomere
478:inotropic
2001:Medicine
1881:Amrinone
1802:Dopamine
1691:Oxedrine
1590:33185990
1551:29707029
1490:Archived
1468:30242219
1411:28082673
1352:35852527
1295:Archived
1264:Archived
1233:21856481
1197:13366846
1189:21856480
1153:19876734
1104:30242219
1045:29867217
996:21415352
936:28775348
840:11805843
764:20498236
690:19234787
460:myocytes
147:DrugBank
136:11689883
52:ATC code
1542:5916097
1459:6155018
1438:Bibcode
1402:5339759
1343:9297119
1241:9411257
1144:2772951
1095:6155018
1072:Bibcode
1036:6092189
987:4090309
966:Bibcode
958:Science
927:5543065
906:Bibcode
848:4337201
820:Bibcode
681:2772957
588:The US
584:History
559:in the
494:calcium
353:401.442
312:Formula
176:9864610
156:DB11816
122:PubChem
68:)
62: (
60:C01CX10
1987:Portal
1951:WHO-EM
1648:agents
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1496:11 May
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812:Nature
762:
714:
688:
678:
539:oxygen
522:ATPase
441:myosin
386:SMILES
227:ChEMBL
216:D09648
1872:PDE3I
1736:mixed
1486:Amgen
1356:S2CID
1237:S2CID
1193:S2CID
844:S2CID
624:(3).
550:that
456:actin
406:InChI
362:JSmol
254:2OW (
1795:Both
1632:C01C
1586:PMID
1547:PMID
1498:2020
1464:PMID
1407:PMID
1348:PMID
1322:JAMA
1303:2022
1272:2022
1229:PMID
1185:PMID
1149:PMID
1100:PMID
1041:PMID
992:PMID
932:PMID
836:PMID
760:PMID
712:ISBN
686:PMID
257:PDBe
207:KEGG
187:UNII
1643:and
1576:hdl
1568:doi
1564:384
1537:PMC
1529:doi
1454:PMC
1446:doi
1397:PMC
1387:doi
1383:292
1338:PMC
1330:doi
1326:328
1221:doi
1217:378
1177:doi
1173:378
1139:PMC
1131:doi
1090:PMC
1080:doi
1031:PMC
1023:doi
982:PMC
974:doi
962:331
922:PMC
914:doi
876:114
828:doi
816:415
791:doi
750:doi
676:PMC
668:doi
626:hdl
433:INN
280:EPA
126:CID
65:WHO
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