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Identification
NameLevosimendan
Accession NumberDB00922  (APRD01296)
TypeSmall Molecule
GroupsApproved, Investigational
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
Synonyms
SynonymLanguageCode
LevosimedanNot AvailableNot Available
LevosimendanumNot AvailableNot Available
SimdaxNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
SimdaxNot Available
SimendanNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number141505-33-1
WeightAverage: 280.2847
Monoisotopic: 280.107259036
Chemical FormulaC14H12N6O
InChI KeyWHXMKTBCFHIYNQ-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
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylhydrazines. These are compounds containing a phenylhydrazide moiety, which consists of a hydrazide substituent attached to a phenyl group.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenylhydrazines
Direct ParentPhenylhydrazines
Alternative Parents
Substituents
  • Phenylhydrazine
  • Pyridazinone
  • Pyridazine
  • Hydrazone
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Nitrile
  • Carbonitrile
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease.
PharmacodynamicsLevosimendan 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 actionLevosimendan 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.
AbsorptionThe bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients.
Volume of distributionNot Available
Protein binding98% bound to plasma protein.
Metabolism

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

SubstrateEnzymesProduct
Levosimendan
Not Available
OR-1855Details
Levosimendan
Not Available
OR-1896Details
Route of eliminationNot Available
Half lifeEliminination half-life is approximately 1 hour.
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9764
Blood Brain Barrier+0.9248
Caco-2 permeable+0.5602
P-glycoprotein substrateNon-substrate0.5083
P-glycoprotein inhibitor INon-inhibitor0.5867
P-glycoprotein inhibitor IINon-inhibitor0.9615
Renal organic cation transporterNon-inhibitor0.8403
CYP450 2C9 substrateNon-substrate0.7037
CYP450 2D6 substrateNon-substrate0.8349
CYP450 3A4 substrateSubstrate0.6149
CYP450 1A2 substrateInhibitor0.8301
CYP450 2C9 substrateNon-inhibitor0.7083
CYP450 2D6 substrateNon-inhibitor0.8979
CYP450 2C19 substrateNon-inhibitor0.5965
CYP450 3A4 substrateNon-inhibitor0.8412
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5918
Ames testNon AMES toxic0.6333
CarcinogenicityNon-carcinogens0.6764
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6188 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9745
hERG inhibition (predictor II)Non-inhibitor0.854
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0881 mg/mLALOGPS
logP2.69ALOGPS
logP2.16ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)10.53ChemAxon
pKa (Strongest Basic)4.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area113.43 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity77.63 m3·mol-1ChemAxon
Polarizability28.67 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Dharmaraj Ramachandra Rao, Rajendra Narayanrao Kankan, Manjinder Singh Phull, Ashwini Amol Sawant, “Process for Preparing Levosimendan and Intermediates for Use in the Process.” U.S. Patent US20120165524, issued June 28, 2012.

US20120165524
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
ATC CodesC01CX08
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (57.1 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Troponin C, slow skeletal and cardiac muscles

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Troponin C, slow skeletal and cardiac muscles P63316 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inducer

Components

Name UniProt ID Details
ATP-sensitive inward rectifier potassium channel 11 Q14654 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inducer

Components

Name UniProt ID Details
ATP-sensitive inward rectifier potassium channel 8 Q15842 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
cGMP-inhibited 3',5'-cyclic phosphodiesterase A Q14432 Details

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12