Identification

Name
Edaravone
Accession Number
DB12243
Type
Small Molecule
Groups
Approved, Investigational
Description

Edaravone is a free radical scavenger approved in May, 2017 for the treatment of amyotrophic lateral scleorosis (ALS). Clinical studies showed that the treatment attenuated deterioration of the disease when compared to placebo. It has been previously investigated for the treatment of ischemic stroke, reperfusion Injury, and myocardial Infarction as it possesses antioxidant and anti-apoptotic properties. Being a low molecular weight molecule with good water and lipid-soluble properies, it is therapeutically advantageous in crossing the blood-brain barrier to mediate nootropic and neuroprotective effects. Oral formulation of edaravone is currently under development.

Structure
Thumb
Synonyms
  • 1-phenyl-3-methyl-5-oxo-2-pyrazoline
  • 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one
  • 3-methyl-1-phenyl-2-pyrazolin-5-one
  • 3-methyl-1-phenyl-5-pyrazolone
  • 3-methyl-1-phenylpyrazol-5-one
  • C.I. developer 1
  • developer Z
  • Edaravone
  • methylphenylpyrazolone
  • norphenazone
  • phenyl methyl pyrazolone
  • phenylmethylpyrazolone
External IDs
MCI-186 / NSC-12 / NSC-26139 / NSC-2629 / TW001
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RadicavaInjection30 mg/100mLIntravenousMitsubishi Tanabe Pharma America, Inc.2017-05-05Not applicableUs
International/Other Brands
Arone (Edinburgh Pharmaceuticals (India)) / Radicut (Mitsubishi Tanabe Pharma Corporation)
Categories
UNII
S798V6YJRP
CAS number
89-25-8
Weight
Average: 174.203
Monoisotopic: 174.07931295
Chemical Formula
C10H10N2O
InChI Key
QELUYTUMUWHWMC-UHFFFAOYSA-N
InChI
InChI=1S/C10H10N2O/c1-8-7-10(13)12(11-8)9-5-3-2-4-6-9/h2-6H,7H2,1H3
IUPAC Name
3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one
SMILES
CC1=NN(C(=O)C1)C1=CC=CC=C1

Pharmacology

Indication

Indicated for improving neurological symptoms and damage from acute ischemic stroke and delaying disease progression of ALS.

Associated Conditions
Pharmacodynamics

Edaravone scavenges free hydroxyl radicals and peroxynitrite radicals which are highly associated with neuronal damage/death from many cerebral vascular disorders such as ischemic strokes and degenerative neurological disorders such as ALS. It exerts a neuroprotective and antioxidant effect and delays disease progression by limiting the extent of lipid peroxidation via free radical generation and cell membrane damage from oxidative stress. It reversed the reduction in regional blood flow and cerebral edema in a case of ischemic stroke.

Mechanism of action

Nootropic and neuroprotective effects are mediated through inhibiting lipid peroxidation and scavenging free radicals. Edaravone acts to increase prostacyclin production, decrease lipoxygenase metabolism of arachidonic acid by trapping hydroxyl radicals, and inhibit alloxan-induced lipid peroxidation and quench active oxygen species. It targets various kinds of cells, including neurons, endothelial cells and myocardial cells [6]. There is also evidence of reduction of neuronal nitric oxide synthase (nNOS) levels and potentiation of SOD1 levels after transient ischemia in rabbits thus preventing spinal cord injury.

Absorption

The peak plasma concentration of the parent drug is reached at the end of infusion, without accumulation of the drug with multiple dosing regimen. The mean Cmax value in healthy male adults is 888ng/mL for intravenous infusion. The values of AUC and Cmax are increased in a dose-proportional relationship. The oral bioavailability in mouse studies is 38% of the I.V. delivery [1].

Volume of distribution

The mean Vd value following an intravenous infusion of a single 30mg dose is 18.5L/kg [2].

Protein binding

The in vitro binding rates of edaravone to human serum protein and albumin are 92% and 89-91%, respectively, with no concentration-dependence.

Metabolism

Multiple renal and hepatic uridine diphosphate glucuronosyltransferase (UGT) isoforms catalyze glucuronidation reaction of edaravone to form glucuronide conjugates. Edaravone is also metabolized into sulfate conjugates via sulfotransferase activity, which is the main metabolite form predominantly found circulating in plasma. It is predicted that the sulfate conjugate is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine. These metabolites have no pharmacological activity.

Route of elimination

About 0.7-0.9% of the dose is excreted as unchanged drug and 71.0-79.9% of the dose is excreted as metabolites (mostly as glucuronide conjugates) through mainly renal elimination.

Half life

The mean terminal elimination half-life of edaravone is 4.5 to 6 hours and the half-lives of its metabolites are 2 to 2.8 hours.

Clearance

The mean total plasma drug clearance following an intravenous infusion of a single 30mg dose is 0.1L/min [2].

Toxicity

No reported evidence of carcinogenic, mutagenic or teratogenic potential. Oral LD50 value is 1,915 mg/kg (Rat). Adverse effects include rashes, hypertension, altered hepatic function, and acute renal impairment. Hematological abnormalities, lung injury and rhabomyolysis may occur with no known incidences.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenThe excretion of Edaravone can be decreased when combined with Acetaminophen.
AcetazolamideThe excretion of Edaravone can be decreased when combined with Acetazolamide.
Acetylsalicylic acidThe excretion of Edaravone can be decreased when combined with Acetylsalicylic acid.
AcyclovirThe excretion of Edaravone can be decreased when combined with Acyclovir.
Adefovir DipivoxilThe excretion of Edaravone can be decreased when combined with Adefovir Dipivoxil.
AlprostadilThe excretion of Edaravone can be decreased when combined with Alprostadil.
Aminohippuric acidThe excretion of Edaravone can be decreased when combined with Aminohippuric acid.
AminophenazoneThe excretion of Edaravone can be decreased when combined with Aminophenazone.
AmoxicillinThe excretion of Edaravone can be decreased when combined with Amoxicillin.
AntipyrineThe excretion of Edaravone can be decreased when combined with Antipyrine.
Food Interactions
Not Available

References

General References
  1. Jiao SS, Yao XQ, Liu YH, Wang QH, Zeng F, Lu JJ, Liu J, Zhu C, Shen LL, Liu CH, Wang YR, Zeng GH, Parikh A, Chen J, Liang CR, Xiang Y, Bu XL, Deng J, Li J, Xu J, Zeng YQ, Xu X, Xu HW, Zhong JH, Zhou HD, Zhou XF, Wang YJ: Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits. Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5225-30. doi: 10.1073/pnas.1422998112. Epub 2015 Apr 6. [PubMed:25847999]
  2. Li H, Xu K, Wang Y, Zhang H, Li T, Meng L, Gong X, Zhang H, Ou N, Ruan J: Phase I clinical study of edaravone in healthy Chinese volunteers: safety and pharmacokinetics of single or multiple intravenous infusions. Drugs R D. 2012 Jun 1;12(2):65-70. doi: 10.2165/11634290-000000000-00000. [PubMed:22762844]
  3. Watanabe T, Tahara M, Todo S: The novel antioxidant edaravone: from bench to bedside. Cardiovasc Ther. 2008 Summer;26(2):101-14. doi: 10.1111/j.1527-3466.2008.00041.x. [PubMed:18485133]
  4. Kikuchi K, Uchikado H, Miyagi N, Morimoto Y, Ito T, Tancharoen S, Miura N, Miyata K, Sakamoto R, Kikuchi C, Iida N, Shiomi N, Kuramoto T, Kawahara K: Beyond neurological disease: new targets for edaravone (Review). Int J Mol Med. 2011 Dec;28(6):899-906. doi: 10.3892/ijmm.2011.795. Epub 2011 Sep 15. [PubMed:21922128]
  5. Kikuchi K, Miura N, Kawahara KI, Murai Y, Morioka M, Lapchak PA, Tanaka E: Edaravone (Radicut), a free radical scavenger, is a potentially useful addition to thrombolytic therapy in patients with acute ischemic stroke. Biomed Rep. 2013 Jan;1(1):7-12. Epub 2012 Aug 29. [PubMed:24648884]
  6. Ikeda K, Iwasaki Y: Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse. PLoS One. 2015 Oct 15;10(10):e0140316. doi: 10.1371/journal.pone.0140316. eCollection 2015. [PubMed:26469273]
  7. Mitsubishi Tanabe Pharma Corporation Radicut Label [Link]
External Links
KEGG Drug
D01552
KEGG Compound
C13008
PubChem Compound
4021
PubChem Substance
347828521
ChemSpider
3881
BindingDB
50200541
ChEBI
31530
ChEMBL
CHEMBL290916
Wikipedia
Edaravone
FDA label
Download (193 KB)
MSDS
Download (27.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedOtherHealthy Volunteers / Impaired Renal Function1
1RecruitingOtherHealthy Volunteers / Hepatic Impairment1
1RecruitingOtherHealthy Volunteers / Severe Hepatic Impairment1
1Unknown StatusTreatmentStrokes1
1, 2RecruitingTreatmentNeuromuscular Diseases1
2CompletedTreatmentAcute Ischemic Stroke (AIS)2
2CompletedTreatmentBrain Necrosis / Nasopharyngeal Carcinoma1
3CompletedTreatmentAcute Ischemic Stroke (AIS)1
3CompletedTreatmentAmyotrophic Lateral Sclerosis (ALS)4
4CompletedTreatmentCerebral Infarctions1
4CompletedTreatmentMyocardial Infarction / Reperfusion Injury1
4CompletedTreatmentStrokes1
Not AvailableNot Yet RecruitingPreventionTransplantation, Kidney1
Not AvailableUnknown StatusPreventionAcute Aortic Dissection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous30 mg/100mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6933310No2005-08-232020-11-13Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)129.7FDA Label
water solubility<1 mg/mLMSDS
pKa7.0Watanabe T, Tahara M, Todo S: The novel antioxidant edaravone: from bench to bedside. Cardiovasc Ther. 2008 Summer;26(2):101-14. doi: 10.1111/j.1527-3466.2008.00041.x. [A19140]
Predicted Properties
PropertyValueSource
Water Solubility0.939 mg/mLALOGPS
logP0.53ALOGPS
logP1.53ChemAxon
logS-2.3ALOGPS
pKa (Strongest Acidic)13.45ChemAxon
pKa (Strongest Basic)-1.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area32.67 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity49.49 m3·mol-1ChemAxon
Polarizability18.61 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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/MSsplash10-004i-1900000000-9c17dd936441a10926dc

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyrazolones. These are compounds containing a pyrazole ring which bears a ketone.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azolines
Sub Class
Pyrazolines
Direct Parent
Pyrazolones
Alternative Parents
Benzene and substituted derivatives / Carboxylic acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Benzenoid / Pyrazolinone / Monocyclic benzene moiety / Azacycle / Carboxylic acid derivative / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound / Organic oxide / Hydrocarbon derivative
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
ring assembly (CHEBI:31530)

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Substrate profile was investigated in vitro using HEK293 cells.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. VanWert AL, Gionfriddo MR, Sweet DH: Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm Drug Dispos. 2010 Jan;31(1):1-71. doi: 10.1002/bdd.693. [PubMed:19953504]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Substrate activity was demonstrated in vitro using HEK293 cells.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. VanWert AL, Gionfriddo MR, Sweet DH: Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm Drug Dispos. 2010 Jan;31(1):1-71. doi: 10.1002/bdd.693. [PubMed:19953504]

Drug created on October 20, 2016 15:42 / Updated on December 16, 2018 06:59