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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
SaltsNot Available
Brand names
NameCompany
SimdaxNot Available
SimendanNot Available
Brand mixturesNot Available
Categories
CAS number141505-33-1
WeightAverage: 280.2847
Monoisotopic: 280.107259036
Chemical FormulaC14H12N6O
InChI KeyInChIKey=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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenylhydrazines
Direct parentPhenylhydrazines
Alternative parentsPyridazinones; Hydrazones; Nitriles; Carboxylic Acid Amides; Polyamines; Imines
Substituentspyridazinone; pyridazine; hydrazone; carboxamide group; carboxylic acid derivative; nitrile; carbonitrile; polyamine; imine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenylhydrazines. These are compounds containing a phenylhydrazide moiety, which consists of an hydrazide substituent attacthed to a phenyl group.
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
    OR-1855Details
    Levosimendan
      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
      Property Value Probability
      Human Intestinal Absorption + 0.9764
      Blood Brain Barrier + 0.9248
      Caco-2 permeable + 0.5602
      P-glycoprotein substrate Non-substrate 0.5083
      P-glycoprotein inhibitor I Non-inhibitor 0.5867
      P-glycoprotein inhibitor II Non-inhibitor 0.9615
      Renal organic cation transporter Non-inhibitor 0.8403
      CYP450 2C9 substrate Non-substrate 0.7037
      CYP450 2D6 substrate Non-substrate 0.8349
      CYP450 3A4 substrate Substrate 0.6149
      CYP450 1A2 substrate Inhibitor 0.8301
      CYP450 2C9 substrate Non-inhibitor 0.7083
      CYP450 2D6 substrate Non-inhibitor 0.8979
      CYP450 2C19 substrate Non-inhibitor 0.5965
      CYP450 3A4 substrate Non-inhibitor 0.8412
      CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5918
      Ames test Non AMES toxic 0.6333
      Carcinogenicity Non-carcinogens 0.6764
      Biodegradation Not ready biodegradable 1.0
      Rat acute toxicity 2.6188 LD50, mol/kg Not applicable
      hERG inhibition (predictor I) Weak inhibitor 0.9745
      hERG inhibition (predictor II) Non-inhibitor 0.854
      Pharmacoeconomics
      ManufacturersNot Available
      PackagersNot Available
      Dosage formsNot Available
      PricesNot Available
      PatentsNot Available
      Properties
      Statesolid
      Experimental PropertiesNot Available
      Predicted Properties
      PropertyValueSource
      water solubility8.81e-02 g/lALOGPS
      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 area113.43ChemAxon
      rotatable bond count3ChemAxon
      refractivity77.63ChemAxon
      polarizability28.67ChemAxon
      number of rings2ChemAxon
      bioavailability1ChemAxon
      rule of fiveYesChemAxon
      Ghose filterYesChemAxon
      Veber's ruleNoChemAxon
      MDDR-like ruleNoChemAxon
      Spectra
      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
      ResourceLink
      PubChem Compound3033825
      PubChem Substance46507149
      ChemSpider2298414
      ChEBI50567
      ChEMBLCHEMBL2051955
      Therapeutic Targets DatabaseDAP000797
      PharmGKBPA164749138
      WikipediaLevosimendan
      ATC CodesC01CX08
      AHFS CodesNot Available
      PDB EntriesNot Available
      FDA labelNot Available
      MSDSshow(57.1 KB)
      Interactions
      Drug InteractionsNot Available
      Food InteractionsNot Available

      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

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