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Levosimendan

Synopsis, Chemistry

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Also known as: 141505-33-1, Simdax, (r)-simendan, (-)-or-1259, Or-1259, Simendan, (r)-

Molecular Formula

C₁₄H₁₂N₆O

Molecular Weight

280.28 g/mol

InChI Key

WHXMKTBCFHIYNQ-SECBINFHSA-N

FDA UNII

C6T4514L4E

A hydrazone and pyridazine derivative; the levo-form is a phosphodiesterase III inhibitor, calcium-sensitizing agent, and inotropic agent that is used in the treatment of HEART FAILURE.

1 2D Structure

Levosimendan

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[[4-[(4R)-4-methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile

2.1.2 InChI

InChI=1S/C14H12N6O/c1-9-6-13(21)19-20-14(9)10-2-4-11(5-3-10)17-18-12(7-15)8-16/h2-5,9,17H,6H2,1H3,(H,19,21)/t9-/m1/s1

2.1.3 InChI Key

WHXMKTBCFHIYNQ-SECBINFHSA-N

2.1.4 Canonical SMILES

CC1CC(=O)NN=C1C2=CC=C(C=C2)NN=C(C#N)C#N

2.1.5 Isomeric SMILES

C[C@@H]1CC(=O)NN=C1C2=CC=C(C=C2)NN=C(C#N)C#N

2.2 Other Identifiers

2.2.1 UNII

C6T4514L4E

2.3 Synonyms

2.3.1 MeSH Synonyms

1. ((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propanedinitrile

2. Dextrosimendan

3. Or 1259

4. Or 1855

5. Or-1259

6. Or-1855

7. Simadax

8. Simendan

2.3.2 Depositor-Supplied Synonyms

1. 141505-33-1

2. Simdax

3. (r)-simendan

4. (-)-or-1259

5. Or-1259

6. Simendan, (r)-

7. Chebi:50567

8. 2-[[4-[(4r)-4-methyl-6-oxo-4,5-dihydro-1h-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile

9. Nsc-759644

10. Levosimedan

11. C6t4514l4e

12. Or1259

13. (r)-((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono) Propanedintrile

14. (r)-n-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbonohydrazonoyl Dicyanide

15. Levosimendan [inn]

16. Dsstox_cid_26445

17. Dsstox_rid_81620

18. Mesoxalonitrile (p-((r)-1,4,5,6-tetrahydro-4-methyl-6-oxo-pyridazinyl)phenyl)hydrazone

19. Dsstox_gsid_46445

20. Levosimendanum

21. Smr002529692

22. Simdax (tn)

23. Cas-141505-33-1

24. Levosimendan (usan/inn)

25. Levosimendan [usan:inn]

26. Or 1259

27. Unii-c6t4514l4e

28. ((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propanedinitrile

29. Levosimendan- Bio-x

30. Levosimendan [mi]

31. Levosimendan [usan]

32. Mesoxalonitrile (-)-(p((r)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazone

33. Schembl83243

34. Levosimendan [mart.]

35. Mls003899227

36. Mls006010741

37. Levosimendan [who-dd]

38. Chembl2051955

39. Dtxsid9046445

40. Levosimendan, >=98% (hplc)

41. Hms3264g03

42. Hms3884n17

43. Kuc109648n

44. Pharmakon1600-01502356

45. Act02710

46. Bcp07048

47. Zinc3915645

48. Tox21_112191

49. Tox21_113768

50. Bdbm50469700

51. Mfcd00867135

52. Nsc759644

53. S2446

54. Akos015895214

55. Tox21_112191_1

56. Ac-1752

57. Am84381

58. Ccg-213048

59. Db00922

60. Ds-8918

61. Nsc 759644

62. ({4-[(4r)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}hydrazono)propanedintrile

63. 2-[[4-[(4r)-4-methyl-6-oxo-4,5-dihydro-1h-pyridazin-3-yl]phenyl]hydrazono]propanedinitrile

64. Ksc-210-010

65. Ncgc00253641-01

66. Ncgc00263564-01

67. Ncgc00263564-02

68. Bm164625

69. Hy-14286

70. L0320

71. Sw219172-1

72. A11874

73. D04720

74. N12889

75. Ab01562970_01

76. Ab01562970_02

77. 741l087

78. A807767

79. Q162541

80. Sr-01000931342

81. Sr-01000931342-2

82. 1-beta-d-ribofuranose-1h-1,2,4-triazole-3-methylcarbonate

83. (r)-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbonohydrazonoyl Dicyanide

84. (r)-n-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbonohydrazonoyldicyanide

85. 1-cyano-n-{4-[(4r)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}methanecarbohydrazonoyl Cyanide

86. 2-(2-(4-((4r)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazinylidene)propanedinitrile

87. Mesoxalonitrile (-)-(p((r)-1,4,5,6-tetrahydro-4-methyl-6- Oxo-3-pyridazinyl)phenyl)hydrazone

88. Propanedinitrile, ((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)-, (r)-

89. Propanedinitrile, 2-(2-(4-((4r)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazinylidene)-

2.4 Create Date

2005-08-08

3 Chemical and Physical Properties

Molecular Formula	C₁₄H₁₂N₆O
Molecular Weight	280.28 g/mol
XLogP3	2.3
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	3
Exact Mass	280.10725903 g/mol
Monoisotopic Mass	280.10725903 g/mol
Topological Polar Surface Area	113 Å²
Heavy Atom Count	21
Formal Charge	0
Complexity	549
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Levosimendan is a new Ca²⁺-sensitizing inotropic agent. Ca²⁺ sensitizers represent a new class of inotropic agents, which overcome the disadvantages associated with currently available inotropic agents in as they are not associated with an increased risk of arrhythmias, cell injury and death due to Ca²⁺ overload in myocardial cells; they do not increase the activation energy; and they have the potential to reverse contractile dysfunction under pathophysiologic conditions, such as acidosis or myocardial stunning. Levosimendan has not been approved for use in the U.S. or Canada.

5.2 MeSH Pharmacological Classification

Vasodilator Agents

Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)

Cardiotonic Agents

Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE). (See all compounds classified as Cardiotonic Agents.)

Phosphodiesterase 3 Inhibitors

Compounds that specifically inhibit PHOSPHODIESTERASE 3. (See all compounds classified as Phosphodiesterase 3 Inhibitors.)

5.3 ATC Code

C - Cardiovascular system

C01 - Cardiac therapy

C01C - Cardiac stimulants excl. cardiac glycosides

C01CX - Other cardiac stimulants

C01CX08 - Levosimendan

5.4 Absorption, Distribution and Excretion

Absorption

The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients.

5.5 Metabolism/Metabolites

Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects.

5.6 Biological Half-Life

Eliminination half-life is approximately 1 hour.

5.7 Mechanism of Action

Levosimendan appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This stabilizes the calcium-induced conformational change of troponin C, thereby (1) changing actin-myosin cross-bridge kinetics apparently without increasing the cycling rate of the cross-bridges or myocardial ATP consumption, (2) increasing the effects of calcium on cardiac myofilaments during systole and (3) improving contraction at low energy cost (inotropic effect). Calcium concentration and, therefore, sensitization decline during diastole, allowing normal or improved diastolic relaxation. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic effect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca²⁺ sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent in experimental animals and humans.