Idebenone

Identification

Name
Idebenone
Accession Number
DB09081
Type
Small Molecule
Groups
Approved, Investigational
Description

Idebenone is a synthetic analogue of ubiquinone (also known as Coenzyme Q10), a vital cell antioxidant and essential component of the Electron Transport Chain (ETC). It has been proposed that by interacting with the ETC, idebenone increases ATP production required for mitochondrial function, reduces free radicals, inhibits lipid peroxidation, and consequently protects the lipid membrane and mitochondria from oxidative damage [2]. More specifically, idebenone is thought to transfer electrons directly to complex III of the mitochondrial ETC, thereby circumventing complex I and restoring cellular energy (ATP) generation [4].

Due to its ability to reduce oxidative damage and improve ATP production, idebenone was originally investigated for its potential use in Alzheimer's Disease and other cognitivie disorders [3]. Lack of improvement in cognitive function halted its production for these conditions, however it continues to be investigated for use in other conditions associated with mitochondrial damage.

Idebenone is currently only indicated for use by the European Medicines Agency (EMA) for the treatment of visual impairment in adolescent and adult patients with Leber’s Hereditary Optic Neuropathy (LHON). LHON is a mitochondrially inherited degeneration of retinal ganglion cells, resulting in acute central vision loss. Due to its biochemical mode of action, it's thought that idebenone may re-activate viable-but-inactive retinal ganglion cells (RGCs) in LHON patients [4]. It is not currently approved for use by either the Food and Drug Administration (USA) or Health Canada.

Structure
Thumb
Synonyms
  • 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone
  • 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-p-benzoquinone
  • 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione
  • 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone
  • 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone
  • 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-p-benzoquinone
  • idébénone
External IDs
BRN 2001459 / BRN-2001459 / BRN2001459 / CV 2619 / CV-2619 / CV2619
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CatenaTablet150 mgOralSanthera Pharmaceuticals (Switzerland) Limited2008-10-152013-04-30Canada
RaxoneTablet, film coated150 mgOralSanthera Pharmaceuticals (Deutschland) Gmb H2015-09-08Not applicableEu
International/Other Brands
Raxone / Sovrima
Categories
UNII
Not Available
CAS number
58186-27-9
Weight
Average: 366.498
Monoisotopic: 366.240624195
Chemical Formula
C21H34O5
InChI Key
VMHWZDULLBLUMS-UHFFFAOYSA-N
InChI
InChI=1S/C21H34O5/c1-16-17(19(24)21(26-3)20(25-2)18(16)23)14-12-10-8-6-4-5-7-9-11-13-15-22/h22H,4-15H2,1-3H3
IUPAC Name
2-(12-hydroxydodecyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione
SMILES
COC1=C(OC)C(=O)C(CCCCCCCCCCCCO)=C(C)C1=O

Pharmacology

Indication

Idebenone is indicated for use by the European Medicines Agency (EMA) for the treatment of visual impairment in adolescent and adult patients with Leber’s Hereditary Optic Neuropathy (LHON). It is not currently approved for use by either the Food and Drug Administration (USA) or Health Canada [4].

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Idebenone is a synthetic analogue of ubiquinone (also known as Coenzyme Q10), a vital cell antioxidant and essential component of the Electron Transport Chain (ETC). It has been proposed that by interacting with the ETC, idebenone increases ATP production required for mitochondrial function, reduces free radicals, inhibits lipid peroxidation, and consequently protects the lipid membrane and mitochondria from oxidative damage [2]. More specifically, idebenone is thought to transfer electrons directly to complex III of the mitochondrial ETC, thereby circumventing complex I and restoring cellular energy (ATP) generation [4].

Absorption

After oral administration, idebenone is rapidly absorbed. On repeat dosing, maximum plasma concentrations of idebenone are reached on average within 1 hour (median 0.67 h range: 0.33-2.00 h). Food increases the bioavailability of idebenone by approximately 5-7-fold and i therefore should always be administered with food [4].

Volume of distribution

Experimental data have shown that idebenone passes the blood-brain barrier and is distributed at significant concentrations in cerebral tissue. Following oral administration pharmacologically relevant concentrations of idebenone are detectable in the aqueous humor of the eye [4].

Protein binding
Not Available
Metabolism

Metabolism occurs by means of oxidative shortening of the side chain and by reduction of the quinone ring and conjugation to glucuronides and sulphates. Idebenone shows a high first pass metabolism resulting in conjugates of idebenone (glucuronides and sulphates (IDE-C)) and the Phase I metabolites QS10, QS6, and QS4 as well as their corresponding Phase II metabolites (glucuronides and sulphates (QS10+QS10-C, QS6+QS6-C, QS4+QS4-C)). The main metabolites in plasma are IDE-C and QS4+QS4-C [4].

Route of elimination

The main route of elimination is metabolism, with the majority of dose excreted via the kidneys as metabolites. After a single or repeated oral dose of 750 mg of idebenone, QS4+QS4-C were the most prominent idebenone-derived metabolites in urine, representing on average between 49.3% and 68.3% of the total administered dose. QS6+QS6 represented 6.45% to 9.46%, whereas QS10+QS10-C and IDE+IDE-C were close to 1% or below [4].

Half life
Not Available
Clearance
Not Available
Toxicity

The most commonly reported adverse reactions to idebenone are mild to moderate diarrhoea (usually not requiring the discontinuation of the treatment), nasopharyngitis, cough and back pain [Label].

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

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Idebenone which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Idebenone which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Idebenone which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Idebenone which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineIdebenone may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Idebenone which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Idebenone which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Idebenone which could result in a higher serum level.
AmpicillinAmpicillin may decrease the excretion rate of Idebenone which could result in a higher serum level.
AuranofinAuranofin may decrease the excretion rate of Idebenone which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Bodmer M, Vankan P, Dreier M, Kutz KW, Drewe J: Pharmacokinetics and metabolism of idebenone in healthy male subjects. Eur J Clin Pharmacol. 2009 May;65(5):493-501. doi: 10.1007/s00228-008-0596-1. Epub 2009 Jan 6. [PubMed:19125241]
  2. Zs -Nagy I: Chemistry, toxicology, pharmacology and pharmacokinetics of idebenone: a review. Arch Gerontol Geriatr. 1990 Nov-Dec;11(3):177-86. [PubMed:15374467]
  3. Gillis JC, Benefield P, McTavish D: Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders. Drugs Aging. 1994 Aug;5(2):133-52. [PubMed:7981485]
  4. EMA Product Label [Link]
External Links
KEGG Drug
D01750
PubChem Compound
12881464
PubChem Substance
310265009
ChemSpider
14944546
ChEBI
31687
ChEMBL
CHEMBL252556
Drugs.com
Drugs.com Drug Page
Wikipedia
Idebenone
ATC Codes
N06BX13 — Idebenone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedOtherDrug-Drug Interaction (DDI)1
1CompletedTreatmentFriedreich's Ataxia2
1, 2CompletedTreatmentMultiple Sclerosis, Primary Progressive1
1, 2Enrolling by InvitationTreatmentDisseminated Sclerosis / Multiple Sclerosis, Primary Progressive1
2CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)2
2CompletedTreatmentFriedreich's Ataxia1
2CompletedTreatmentLeber's Hereditary Optic Neuropathy (LHON)1
2CompletedTreatmentMELAS Syndrome1
3CompletedTreatmentAmbulatory Care / Muscular Dystrophy, Duchenne1
3CompletedTreatmentFreidreich's Ataxia1
3CompletedTreatmentFriedreich's Ataxia4
3WithdrawnNot AvailableLeber's Hereditary Optic Neuropathy (LHON)1
4RecruitingTreatmentLeber's Hereditary Optic Neuropathy (LHON)1
Not AvailableAvailableNot AvailableDuchenne's Muscular Dystrophy (DMD)1
Not AvailableRecruitingNot AvailableLeber's Hereditary Optic Neuropathy (LHON)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral150 mg
Tablet, film coatedOral150 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00747 mg/mLALOGPS
logP4.5ALOGPS
logP4.46ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)16.84ChemAxon
pKa (Strongest Basic)-2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area72.83 Å2ChemAxon
Rotatable Bond Count14ChemAxon
Refractivity105.72 m3·mol-1ChemAxon
Polarizability43.87 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as ubiquinones. These are coenzyme Q derivatives containing a 5, 6-dimethoxy-3-methyl(1,4-benzoquinone) moiety to which an isoprenyl group is attached at ring position 2(or 6).
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Quinone and hydroquinone lipids
Direct Parent
Ubiquinones
Alternative Parents
Long-chain fatty alcohols / P-benzoquinones / Vinylogous esters / Primary alcohols / Organic oxides / Hydrocarbon derivatives
Substituents
Ubiquinone skeleton / Long chain fatty alcohol / Fatty alcohol / P-benzoquinone / Quinone / Fatty acyl / Vinylogous ester / Ketone / Cyclic ketone / Hydrocarbon derivative
Molecular Framework
Aliphatic homomonocyclic compounds
External Descriptors
Not Available

Drug created on August 28, 2015 16:33 / Updated on August 02, 2018 06:13