1-cyano-N-{4-[(4R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}methanecarbohydrazonoyl cyanide

• ChemBase ID: 798
• Molecular Formular: C14H12N6O
• Molecular Mass: 280.28468
• Monoisotopic Mass: 280.10725903
• SMILES: O=C1NN=C([C@@H](C1)C)c1ccc(NN=C(C#N)C#N)cc1
• Canonical SMILES: N#CC(=NNc1ccc(cc1)C1=NNC(=O)C[C@H]1C)C#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
• InChIKey: WHXMKTBCFHIYNQ-SECBINFHSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 1-cyano-N-{4-[(4R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}methanecarbohydrazonoyl cyanide
• IUPAC Traditional name: levosimendan
• Brand Name: Simendan; Simdax
• Synonyms: (-)-OR-1259; (R)-Simendan; 2-[2-[4-[(4R)-1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl]phenyl]hydrazinylidene]-propanedinitrile; OR 1259; R)-((4-(1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono) propanedintrile; Levosimendan; [[4-[(4R)-1,4,5,6-Terahydro-4-methyl-6-oxo-3-pyridazinyl]phenyl]hydrazono]propanedinitrile; OR-1259; Simdax; Levosimedan; Levosimendan

Database IDs

• CAS Number: 141505-33-1
• MDL Number: MFCD00867135
• PubChem SID: 46507149; 160964261
• PubChem CID: 3033825

CALCULATED PROPERTIES

JChem

• Acid pKa: 10.534338
• H Acceptors: 6
• H Donor: 2
• LogD (pH = 5.5): 2.0628319
• LogD (pH = 7.4): 2.159906
• Log P: 2.1616182
• Molar Refractivity: 77.6308 cm^3
• Polarizability: 27.841526 Å^3
• Polar Surface Area: 113.43 Å^2
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.69
• LOG S: -3.5
• Solubility (Water): 8.81e-02 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; DMSO: ≥20 mg/mL; Methanol
• Apperance: yellow powder; Yellow Solid
• Melting Point: 216-219°C (dec.)
• Optical Rotation: [α]/D -500 to -650°, c = 0.5 in THF

Safety Information

• Storage Condition: -20°C Freezer
• RTECS: TY1570210
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 20/21/22
• Safety Statements: 36/37
• GHS Pictograms: GHS07
• GHS Signal Word: Warning
• GHS Hazard statements: H302-H312-H332
• GHS Precautionary statements: P280
• Storage Temperature: room temp

Product Information

• Purity: ≥98% (HPLC)
• Empirical Formula (Hill Notation): C14H12N6O

DETAILS

DrugBank - DB00922

• Drug 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.
• Indication: For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease.
• Pharmacology: Levosimendan is a new Ca^2+-sensitizing inotropic agent. Ca^2+ 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 Ca^2+ 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.
• Affected Organisms: Humans and other mammals
• Biotransformation: Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects.
• Absorption: The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients.
• Half Life: Eliminination half-life is approximately 1 hour.
• Protein Binding: 98% bound to plasma protein.
• References: [Link] ; 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] ; 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: Wikipedia

Sigma Aldrich - L5545

Biochem/physiol Actions
Levosimendan is a calcium sensitiser. The compound increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan binds to cardiac troponin C in a calcium-dependent manner and stabilizes troponin C. This is followed by actin-myosin cross-bridges, without increasing myocardial consumption of ATP. Additionally the compound acts as vasodilator by opening an ATP-sensitive potassium channels. Levosimendan is a drug used for treatment of congestive heart failure. Also it can be used to treat calcium channel blocker overdose.

Toronto Research Chemicals - L378000

Bioactive enantiomer of racemate, Simendan. Positive inotropic agent with vasodilating activity. Cardiotonic.

REFERENCES

• Link
• 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
• Kasikcioglu HA, Cam N: A review of levosimendan in the treatment of heart failure. Vasc Health Risk Manag. 2006;2(4):389-400. Pubmed
• Sandell, E.-P., et al.: J. Cardiovasc. Pharmacol., 26, S57 (1995)
• Pagel, P.S., et al.: Cardiovasc. Drug Rev., 14, 286 (1995)