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Levosimendan

Levosimendan structure

CAS No:
141505-33-1
Formula:
C14H12N6O
Chemical Name:
Levosimendan
Synonyms:
Propanedinitrile,2-[2-[4-[(4R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl]phenyl]hydrazinylidene]-;Propanedinitrile,[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]-,(R)-;Propanedinitrile,[[4-[(4R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl]phenyl]hydrazono]-;2-[2-[4-[(4R)-1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl]phenyl]hydrazinylidene]propanedinitrile;Levosimendan;(R)-Simendan;OR 1259;Simdax;(-)-OR 1259;2-[[4-[(4R)-4-Methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile
Categories:
Active Pharmaceutical Ingredients > Circulatory System Drugs

Description

Yellow Crystalline PowderLevosimendan was introduced in Sweden as an i.v. infusion for the treatment of acute heart failure or refractory symptoms of chronic heart failure in cases where conventional treatment (e.g., diuretic or ACE inhibitor) is not sufficient. Levosimendan is the (R)- enantiomer of simendan that belongs to the same class as pimobendan (Boehringer Ingelheim). Levosimendan is an innovative myofilament calcium sensitizer that increases myocardial contractility by selectivel

Solid

Levosimendan is a hydrazone, a pyridazinone and a nitrile. It has a role as a vasodilator agent, an EC 3.1.4.17 (3',5'-cyclic-nucleotide phosphodiesterase) inhibitor, a cardiotonic drug and an anti-arrhythmia drug.|Levosimendan increases calcium sensitivity to myocytes by binding to troponin C in a calcium dependent manner. This increases contractility without raising calcium levels. It also relaxes vascular smooth muscle by opening adenosine triphosphate sensitive potassium channels. Levosimendan is used to manage acutely decompensated congestive heart failure.|A hydrazone and pyridazine derivative; the levo-form is a phosphodiesterase III inhibitor, calcium-sensitizing agent, and inotropic agent that is used in the treatment of HEART FAILURE.

Levosimendan Basic Attributes

Molecular Weight：

280.28

Exact Mass：

280.28

EC Number：

1308068-626-2

UNII：

C6T4514L4E

NSC Number：

759644

DSSTox ID：

DTXSID9046445

ATC Code：

C - Cardiovascular system

Characteristics

PSA：

113

XLogP3：

2.3

Appearance：

yellow

Density：

1.33±0.1 g/cm3(Predicted)

Melting Point：

216-219°C (dec.)

Refractive Index：

1.673

Water Solubility：

DMSO: ≥20mg/mL

Storage Conditions：

-20°C Freezer

Toxicity：

LD50 in male, female mice, male rats (mg/kg): 156, 152, 103 orally; 32, 50, 57 i.v. (Pagel)

Specific rotation：

D25 -566° (tetrahydrofurane/methanol)

Safety Information

Transport codes：

NONH for all modes of transport

wgk germany：

hazard class code：

20/21/22

safety instructions：

36/37

RTECS Number：

TY1570210

Marks：

Precautionary statement(s)：

P280

Hazard Statements：

H302-H312-H332

GHS Classification：

|Warning|H302 (95.12%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P322, P330, P363, and P501|Aggregated GHS information provided by 41 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Toxicity

Protein Binding：

98% bound to plasma protein.

Drug Information

Drug 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 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.

MeSH：

Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)|Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE). (See all compounds classified as Cardiotonic Agents.)|Compounds that specifically inhibit PHOSPHODIESTERASE 3. (See all compounds classified as Phosphodiesterase 3 Inhibitors.)

Absorption：

The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients.

Metabolism/Metabolites：

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

Biological Half-Life：

Eliminination half-life is approximately 1 hour.

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.

MeSH Entry Terms：

((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propanedinitrile

Levosimendan Use and Manufacturing

Uses

anesthetic

Use Classification：

Human drugs -> Rare disease (orphan)

Computed Properties

Molecular Weight:280.28
XLogP3:2.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:280.10725903
Monoisotopic Mass:280.10725903
Topological Polar Surface Area:113
Heavy Atom Count:21
Complexity:549
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

Material

Sodium acetate trihydrate

Drug Function and Efficacy

Extract from the above information

This ingredient has been used in drugs with the following functions (note: it does not mean that the ingredient itself has the following health functions)

Related Drugs

Levosimendan Injection
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Registered Holders

Fermion Oy

Finland
Active
Chengdu Sino-Strong Pharmaceutical Co., Ltd.

China
Active
Chengdu Shengnuo Biopharm Co., Ltd.

China
Active

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