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Identification
Name Levosimendan
Accession Number DB00922 (APRD01296)
Type small molecule
Groups approved
Description

Levosimendan is a calcium sensitiser used in the management of acutely decompensated congestive heart failure. It increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan exerts its effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C in a calcium-dependent manner. It also has a vasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Levosimedan
Salts Not Available
Brand names
Name Company
Simdax
Simendan
Brand mixtures Not Available
Categories
  • Vasodilator Agents
  • Phosphodiesterase Inhibitors
  • Cardiotonic Agents
  • Anti-Arrhythmia Agents
CAS number 141505-33-1
Weight Average: 280.2847
Monoisotopic: 280.107259036
Chemical Formula C14H12N6O
InChI Key InChIKey=WHXMKTBCFHIYNQ-SECBINFHSA-N
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
Plain Text
IUPAC Name
1-cyano-N-{4-[(4R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}methanecarbohydrazonoyl cyanide
SMILES
C[C@@H]1CC(=O)NN=C1C1=CC=C(NN=C(C#N)C#N)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Pyridazines
  • Phenylhydrazines
  • Anilines
Substructures
  • Hydrazones
  • Amino Ketones
  • Nitriles and Derivatives
  • Benzene and Derivatives
  • Pyridazines
  • Cyanides
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Hydrazine Derivatives
  • Imines
  • Phenylhydrazines
  • Anilines
Pharmacology
Indication For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease.
Pharmacodynamics 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.
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.
Absorption The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients.
Volume of distribution Not Available
Protein binding 98% bound to plasma protein.
Metabolism Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects.
Route of elimination Not Available
Half life Eliminination half-life is approximately 1 hour.
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms Not Available
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 8.81e-02 g/l ALOGPS
logP 2.69 ALOGPS
logP 2.16 ChemAxon
logS -3.5 ALOGPS
pKa (strongest acidic) 10.53 ChemAxon
pKa (strongest basic) 4.91 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 6 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 113.43 ChemAxon
rotatable bond count 3 ChemAxon
refractivity 77.63 ChemAxon
polarizability 28.67 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Link
  2. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, Thakkar R, Padley RJ, Poder P, Kivikko M: Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007 May 2;297(17):1883-91. Pubmed
  3. Kasikcioglu HA, Cam N: A review of levosimendan in the treatment of heart failure. Vasc Health Risk Manag. 2006;2(4):389-400. Pubmed
External Links
Resource Link
PubChem Compound 3033825 Link_out
PubChem Substance 46507149 Link_out
ChemSpider 2298414 Link_out
ChEBI 50567 Link_out
ChEMBL 50567 Link_out
Therapeutic Targets Database DAP000797 Link_out
PharmGKB PA164749138 Link_out
Wikipedia http://en.wikipedia.org/wiki/Levosimendan Link_out
ATC Codes
  • C01CX08
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (57.1 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Troponin C, slow skeletal and cardiac muscles

Pharmacological action: yes
Actions: potentiator

Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components:Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments

Organism class: human
UniProt ID: P63316 Link_out
Gene: TNNC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kleerekoper Q, Putkey JA: Drug binding to cardiac troponin C. J Biol Chem. 1999 Aug 20;274(34):23932-9. Pubmed
  2. Levijoki J, Pollesello P, Kaivola J, Tilgmann C, Sorsa T, Annila A, Kilpelainen I, Haikala H: Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analysis with analogs of levosimendan. J Mol Cell Cardiol. 2000 Mar;32(3):479-91. Pubmed
  3. Sorsa T, Heikkinen S, Abbott MB, Abusamhadneh E, Laakso T, Tilgmann C, Serimaa R, Annila A, Rosevear PR, Drakenberg T, Pollesello P, Kilpelainen I: Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem. 2001 Mar 23;276(12):9337-43. Epub 2000 Dec 11. Pubmed
  4. Sorsa T, Pollesello P, Permi P, Drakenberg T, Kilpelainen I: Interaction of levosimendan with cardiac troponin C in the presence of cardiac troponin I peptides. J Mol Cell Cardiol. 2003 Sep;35(9):1055-61. Pubmed
  5. Lehmann A, Boldt J, Lang J, Isgro F, Blome M: [Is levosimendan an inoprotective drug in patients with acute coronary syndrome undergoing surgical revascularization?] Anasthesiol Intensivmed Notfallmed Schmerzther. 2003 Sep;38(9):577-82. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. ATP-sensitive inward rectifier potassium channel 11

Pharmacological action: yes
Actions: inducer

This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium

Organism class: human
UniProt ID: Q14654 Link_out
Gene: KCNJ11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yildiz O: Vasodilating mechanisms of levosimendan: involvement of K+ channels. J Pharmacol Sci. 2007 May;104(1):1-5. Epub 2007 Apr 24. Pubmed

3. ATP-sensitive inward rectifier potassium channel 8

Pharmacological action: yes
Actions: inducer

This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium (By similarity)

Organism class: human
UniProt ID: Q15842 Link_out
Gene: KCNJ8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yildiz O: Vasodilating mechanisms of levosimendan: involvement of K+ channels. J Pharmacol Sci. 2007 May;104(1):1-5. Epub 2007 Apr 24. Pubmed

4. cGMP-inhibited 3',5'-cyclic phosphodiesterase A

Pharmacological action: unknown
Actions: inhibitor

Hydrolyzes both cyclic AMP (cAMP) and cyclic GMP (cGMP)

Organism class: human
UniProt ID: Q14432 Link_out
Gene: PDE3A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Szilagyi S, Pollesello P, Levijoki J, Haikala H, Bak I, Tosaki A, Borbely A, Edes I, Papp Z: Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone. J Cardiovasc Pharmacol. 2005 Sep;46(3):369-76. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19