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Identification
NameRiluzole
Accession NumberDB00740  (APRD00145)
TypeSmall Molecule
GroupsApproved, Investigational
Description

A glutamate antagonist (receptors, glutamate) used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
RilutekNot AvailableNot Available
RiluzolGerman/SpanishINN
RiluzoleFrenchINN
RiluzolumLatinINN
Salts
Name/CAS Structure Properties
Riluzole Hydrochloride
Thumb
  • InChI Key: QEAOELIJQRYJJS-UHFFFAOYSA-N
  • Monoisotopic Mass: 269.984145836
  • Average Mass: 270.659
DBSALT000679
Brand names
NameCompany
FanizanActavis
LaidecSun Pro
LizolorolActavis
Lizorololratiopharm
RilustadSTADA
RilutekSanofi-Aventis
ScleficActavis
Xie Yi LiLunan Pharm
ZolerilisActavis
Brand mixturesNot Available
CategoriesNot Available
CAS number1744-22-5
WeightAverage: 234.198
Monoisotopic: 234.007468097
Chemical FormulaC8H5F3N2OS
InChI KeyFTALBRSUTCGOEG-UHFFFAOYSA-N
InChI
InChI=1S/C8H5F3N2OS/c9-8(10,11)14-4-1-2-5-6(3-4)15-7(12)13-5/h1-3H,(H2,12,13)
IUPAC Name
6-(trifluoromethoxy)-1,3-benzothiazol-2-amine
SMILES
NC1=NC2=C(S1)C=C(OC(F)(F)F)C=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzothiazoles
SubclassNot Available
Direct parentBenzothiazoles
Alternative parentsPhenol Ethers; Primary Aromatic Amines; Aminothiazoles; Polyamines; Ethers; Organofluorides; Alkyl Fluorides
Substituentsphenol ether; primary aromatic amine; benzene; 1,3-thiazolamine; azole; thiazole; ether; polyamine; organonitrogen compound; amine; organofluoride; organohalogen; primary amine; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the benzothiazoles. These are organic compounds containing a benzene fused to a thiazole ring (a five-member ring with four carbon atoms, one nitrogen atom and one sulfur atom).
Pharmacology
IndicationFor the treatment of amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease)
PharmacodynamicsRiluzole, a member of the benzothiazole class, is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole extends survival and/or time to tracheostomy. It is also neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. The etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS the enzyme superoxide dismutase has been found to be defective.
Mechanism of actionThe mode of action of riluzole is unknown. Its pharmacological properties include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release (activation of glutamate reuptake), 2) inactivation of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors.
AbsorptionRiluzole is well-absorbed (approximately 90%), with average absolute oral bioavailability of about 60% (CV=30%). A high fat meal decreases absorption, reducing AUC by about 20% and peak blood levels by about 45%.
Volume of distributionNot Available
Protein binding96% bound to plasma proteins, mainly to albumin and lipoprotein over the clinical concentration range.
Metabolism

Riluzole is extensively metabolized to six major and a number of minor metabolites, which have not all been identified to date. Metabolism is mostly hepatic, consisting of cytochrome P450–dependent hydroxylation and glucuronidation. CYP1A2 is the primary isozyme involved in N-hydroxylation; CYP2D6, CYP2C19, CYP3A4, and CYP2E1 are considered unlikely to contribute significantly to riluzole metabolism in humans.

Route of eliminationNot Available
Half lifeThe mean elimination half-life of riluzole is 12 hours (CV=35%) after repeated doses.
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.995
Blood Brain Barrier + 0.9799
Caco-2 permeable - 0.5377
P-glycoprotein substrate Non-substrate 0.8045
P-glycoprotein inhibitor I Non-inhibitor 0.8245
P-glycoprotein inhibitor II Non-inhibitor 0.6998
Renal organic cation transporter Non-inhibitor 0.859
CYP450 2C9 substrate Non-substrate 0.8679
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.7032
CYP450 1A2 substrate Inhibitor 0.9106
CYP450 2C9 substrate Non-inhibitor 0.9072
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8332
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6647
Ames test AMES toxic 0.6799
Carcinogenicity Non-carcinogens 0.9001
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 3.6843 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9775
hERG inhibition (predictor II) Non-inhibitor 0.8734
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • Impax laboratories inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Rilutek 50 mg tablet18.77USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States55278141993-06-182013-06-18
Canada21516042005-09-202013-12-10
Canada21174662000-01-252012-10-22
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point119 °CNot Available
logP2.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0395ALOGPS
logP2.83ALOGPS
logP3.4ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)16.44ChemAxon
pKa (Strongest Basic)4.57ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area48.14 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity44.37 m3·mol-1ChemAxon
Polarizability18.59 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Pratap Padi, Madhusudhan Ganta, Satyanarayana Bollikonda, Sridhar Chaganti, Ramulu Akula, Loka Maheshwari Dommati, “PROCESS FOR PREPARING RILUZOLE.” U.S. Patent US20080108827, issued May 08, 2008.

US20080108827
General Reference
  1. Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T: Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther. 1997 Aug;282(2):707-14. Pubmed
  2. Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, Saksa J, Wu YT, Gueorguieva R, Sanacora G, Malison RT, Krystal JH: Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005 Sep 1;58(5):424-8. Pubmed
  3. van Kan HJ, Groeneveld GJ, Kalmijn S, Spieksma M, van den Berg LH, Guchelaar HJ: Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis. Br J Clin Pharmacol. 2005 Mar;59(3):310-3. Pubmed
  4. Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK: An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004 Jan;161(1):171-4. Pubmed
  5. Mathew SJ, Manji HK, Charney DS: Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92. Epub 2008 Jan 2. Pubmed
  6. Lamanauskas N, Nistri A: Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci. 2008 May;27(10):2501-14. Epub 2008 Apr 26. Pubmed
External Links
ResourceLink
KEGG DrugD00775
KEGG CompoundC07937
PubChem Compound5070
PubChem Substance46508094
ChemSpider4892
BindingDB30705
Therapeutic Targets DatabaseDAP000527
PharmGKBPA451251
IUPHAR2326
Guide to Pharmacology2326
Drug Product Database2242763
RxListhttp://www.rxlist.com/cgi/generic3/riluzole.htm
Drugs.comhttp://www.drugs.com/cdi/riluzole.html
WikipediaRiluzole
ATC CodesN07XX02
AHFS Codes
  • 28:92.00
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Sodium channel protein type 5 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 5 subunit alpha Q14524 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Schwartz G, Fehlings MG: Secondary injury mechanisms of spinal cord trauma: a novel therapeutic approach for the management of secondary pathophysiology with the sodium channel blocker riluzole. Prog Brain Res. 2002;137:177-90. Pubmed
  4. Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T: Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther. 1997 Aug;282(2):707-14. Pubmed
  5. Weiss S, Benoist D, White E, Teng W, Saint DA: Riluzole protects against cardiac ischaemia and reperfusion damage via block of the persistent sodium current. Br J Pharmacol. 2010 Jul;160(5):1072-82. Pubmed

2. Cystine/glutamate transporter

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inducer

Components

Name UniProt ID Details
Cystine/glutamate transporter Q9UPY5 Details

References:

  1. Wokke J: Riluzole. Lancet. 1996 Sep 21;348(9030):795-9. Pubmed
  2. Azbill RD, Mu X, Springer JE: Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res. 2000 Jul 21;871(2):175-80. Pubmed
  3. Dunlop J, Beal McIlvain H, She Y, Howland DS: Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. J Neurosci. 2003 Mar 1;23(5):1688-96. Pubmed
  4. Gosselin RD, O’Connor RM, Tramullas M, Julio-Pieper M, Dinan TG, Cryan JF: Riluzole normalizes early-life stress-induced visceral hypersensitivity in rats: role of spinal glutamate reuptake mechanisms. Gastroenterology. 2010 Jun;138(7):2418-25. Epub 2010 Mar 10. Pubmed
  5. Hayashida K, Parker RA, Eisenach JC: Activation of glutamate transporters in the locus coeruleus paradoxically activates descending inhibition in rats. Brain Res. 2010 Mar 4;1317:80-6. Epub 2010 Jan 6. Pubmed

Enzymes

1. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. Pubmed
  2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Transporters

1. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. Milane A, Vautier S, Chacun H, Meininger V, Bensimon G, Farinotti R, Fernandez C: Interactions between riluzole and ABCG2/BCRP transporter. Neurosci Lett. 2009 Mar 6;452(1):12-6. Epub 2009 Jan 6. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on January 07, 2014 09:22