Identification

Name
Levosimendan
Accession Number
DB00922  (APRD01296)
Type
Small Molecule
Groups
Approved, 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
  • Levosimedan
  • Levosimendanum
  • Simdax
External IDs
(-)-OR-1259
International/Other Brands
Simdax / Simendan
Categories
UNII
C6T4514L4E
CAS number
141505-33-1
Weight
Average: 280.2847
Monoisotopic: 280.107259036
Chemical Formula
C14H12N6O
InChI Key
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

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.

TargetActionsOrganism
ATroponin C, slow skeletal and cardiac muscles
potentiator
Human
AATP-sensitive inward rectifier potassium channel 11
inducer
Human
AATP-sensitive inward rectifier potassium channel 8
inducer
Human
UcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Human
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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololThe risk or severity of adverse effects can be increased when Levosimendan is combined with Acebutolol.
AldesleukinThe risk or severity of adverse effects can be increased when Levosimendan is combined with Aldesleukin.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Levosimendan.
AliskirenThe risk or severity of adverse effects can be increased when Levosimendan is combined with Aliskiren.
AmifostineThe risk or severity of adverse effects can be increased when Amifostine is combined with Levosimendan.
AmilorideThe risk or severity of adverse effects can be increased when Levosimendan is combined with Amiloride.
AmiodaroneThe risk or severity of adverse effects can be increased when Amiodarone is combined with Levosimendan.
AmitriptylineThe risk or severity of QTc prolongation can be increased when Amitriptyline is combined with Levosimendan.
AmlodipineThe risk or severity of adverse effects can be increased when Levosimendan is combined with Amlodipine.
AmobarbitalAmobarbital may increase the hypotensive activities of Levosimendan.
Food Interactions
Not 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 References
  1. 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:17473298]
  2. Kasikcioglu HA, Cam N: A review of levosimendan in the treatment of heart failure. Vasc Health Risk Manag. 2006;2(4):389-400. [PubMed:17323593]
External Links
Human Metabolome Database
HMDB0015058
PubChem Compound
3033825
PubChem Substance
46507149
ChemSpider
2298414
ChEBI
50567
ChEMBL
CHEMBL2051955
Therapeutic Targets Database
DAP000797
PharmGKB
PA164749138
Wikipedia
Levosimendan
ATC Codes
C01CX08 — Levosimendan
MSDS
Download (57.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentLow Cardiac Output Syndrome1
2CompletedPreventionDefect, Congenital Heart1
2CompletedPreventionHeart Failure, Unspecified1
2CompletedTreatmentAmyotrophic Lateral Sclerosis (ALS)1
2CompletedTreatmentChronic Heart Failure (CHF) / Heart Diseases1
2CompletedTreatmentCoronary Heart Disease (CHD)1
2CompletedTreatmentHeart Failure, Unspecified1
2CompletedTreatmentLow Cardiac Output Syndrome1
2CompletedTreatmentShock, Septic1
2CompletedTreatmentStrokes / Transient Ischaemic Attack (TIA)1
2Not Yet RecruitingTreatmentHeart Failure With Normal Ejection Fraction / Hypertension Pulmonary Secondary Heart Failure / Right Sided Heart Failure With Normal Ejection Fraction1
2TerminatedTreatmentAcute Heart Failure (AHF)1
2Unknown StatusTreatmentLow Cardiac Output Syndrome1
2, 3Active Not RecruitingTreatmentAcute Kidney Injury (AKI)1
2, 3RecruitingTreatmentMuscle Weakness Conditions / Weaning Failure1
2, 3Unknown StatusTreatmentShock, Cardiogenic / Shock, Septic1
3CompletedPreventionCoronary Artery Bypass Grafting (CABG) Surgery / Left Ventricular Dysfonction1
3CompletedPreventionCoronary Artery Bypass Grafting (CABG) Surgery / Low Cardiac Output Syndrome / Mitral Valve Surgery1
3CompletedTreatmentAcute Heart Failure (AHF)1
3CompletedTreatmentCongestive Heart Failure (CHF)1
3Enrolling by InvitationTreatmentCardiorenal Syndrome1
3Not Yet RecruitingTreatmentAcute Decompensated Heart Failure (ADHF)1
3RecruitingTreatmentAmyotrophic Lateral Sclerosis (ALS)1
3RecruitingTreatmentHeart Failure, Unspecified1
3SuspendedTreatmentAdvanced Chronic Heart Failure1
3TerminatedTreatmentHeart Failure, Unspecified1
3Unknown StatusTreatmentStable Chronic Heart Failure1
4CompletedPreventionMitral Valve Stenosis With Incompetence or Regurgitation1
4CompletedPreventionSurgery, Cardiac1
4CompletedTreatmentCardiopulmonary Bypass Graft1
4CompletedTreatmentCoronary Artery Disease1
4CompletedTreatmentHeart Failure, Unspecified4
4CompletedTreatmentHeart Failure, Unspecified / Myocardial Infarction / Shock, Cardiogenic1
4CompletedTreatmentHeart Valve Disease1
4CompletedTreatmentLow Cardiac Output Syndrome1
4CompletedTreatmentMyocardial Protection1
4Not Yet RecruitingTreatmentHeart Failure, Unspecified1
4RecruitingTreatmentAcute Kidney Injury (AKI) / Renal Insufficiency, Acute1
4RecruitingTreatmentProphylaxis of cardiomyopathy / Shock, Septic1
4SuspendedTreatmentMyocardial Stunning1
4TerminatedTreatmentDiastolic Dysfunction / Left Ventricular Hypertrophy1
4Unknown StatusSupportive CareCardiovascular Disease (CVD)1
4Unknown StatusTreatmentAdvanced Heart Failure1
4WithdrawnTreatmentHeart Failure, Unspecified / Hip Fractures1
Not AvailableCompletedNot AvailableTreatment of Left Heart Insufficiency in an Operative Setting of Cardiac Surgery1
Not AvailableCompletedTreatmentAortic Valve Stenosis / Heart Failure, Diastolic / Physiologic Monitoring / Physiology1
Not AvailableCompletedTreatmentCongenital Cardiovascular Defects / Low Cardiac Output Syndrome1
Not AvailableCompletedTreatmentRespiratory Muscle Function1
Not AvailableNo Longer AvailableNot AvailableHeart Decompensation / Pedaitric Patients With Acute on Chronic Decompensated Heart Failure OR Unable to Wean From ECMO Support1
Not AvailableNot Yet RecruitingTreatmentMyocardial Infarction / Outcomes1
Not AvailableRecruitingNot AvailableBiventricular Failure / Right Ventricular Dysfunction / Symptomatic left ventricular ejection fraction ≤ 35% Chronic heart failure1
Not AvailableRecruitingPreventionHip Fractures / Ventricular Dysfunction, Left1
Not AvailableRecruitingScreeningShock, Septic1
Not AvailableTerminatedTreatmentHeart Failure, Unspecified / Surgery, Cardiac1

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
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 inhibitorNon-inhibitor0.7083
CYP450 2D6 inhibitorNon-inhibitor0.8979
CYP450 2C19 inhibitorNon-inhibitor0.5965
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001i-0390000000-88e46fb95115eb7b2d26

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenylhydrazines
Direct Parent
Phenylhydrazines
Alternative Parents
Pyridazinones / Nitriles / Hydrazones / Carboxylic acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Phenylhydrazine / Pyridazinone / Pyridazine / Carboxylic acid derivative / Hydrazone / Carbonitrile / Nitrile / Organoheterocyclic compound / Azacycle / Organic nitrogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
nitrile, pyridazinone, hydrazone (CHEBI:50567)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Potentiator
General Function
Troponin t binding
Specific Function
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 fo...
Gene Name
TNNC1
Uniprot ID
P63316
Uniprot Name
Troponin C, slow skeletal and cardiac muscles
Molecular Weight
18402.36 Da
References
  1. Kleerekoper Q, Putkey JA: Drug binding to cardiac troponin C. J Biol Chem. 1999 Aug 20;274(34):23932-9. [PubMed:10446160]
  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:10731446]
  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:11113122]
  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:12967628]
  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:12975736]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Voltage-gated potassium channel activity
Specific Function
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 ...
Gene Name
KCNJ11
Uniprot ID
Q14654
Uniprot Name
ATP-sensitive inward rectifier potassium channel 11
Molecular Weight
43540.375 Da
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:17452812]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Inward rectifier potassium channel activity
Specific Function
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...
Gene Name
KCNJ8
Uniprot ID
Q15842
Uniprot Name
ATP-sensitive inward rectifier potassium channel 8
Molecular Weight
47967.455 Da
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:17452812]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
Gene Name
PDE3A
Uniprot ID
Q14432
Uniprot Name
cGMP-inhibited 3',5'-cyclic phosphodiesterase A
Molecular Weight
124978.06 Da
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:16116344]

Drug created on June 13, 2005 07:24 / Updated on August 02, 2018 04:29