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Identification
Name Riluzole
Accession Number DB00740 (APRD00145)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Rilutek
Riluzole HCl
Brand mixtures Not Available
Categories
  • Anticonvulsants
  • Neuroprotective Agents
  • Anesthetics
  • Excitatory Amino Acid Antagonists
CAS number 1744-22-5
Weight Average: 234.198
Monoisotopic: 234.007468097
Chemical Formula C8H5F3N2OS
InChI Key InChIKey=FTALBRSUTCGOEG-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)
Plain Text
IUPAC Name
6-(trifluoromethoxy)-1,3-benzothiazol-2-amine
SMILES
NC1=NC2=C(S1)C=C(OC(F)(F)F)C=C2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Anisoles
  • Benzothiazoles
Substructures
  • Phenols and Derivatives
  • Aliphatic and Aryl Amines
  • Ethers
  • Halogen Derivatives
  • Benzene and Derivatives
  • Thiazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Benzothiazoles
  • Phenyl Esters
Pharmacology
Indication For the treatment of amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease)
Pharmacodynamics Riluzole, 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 action The 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.
Absorption Riluzole 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 distribution Not Available
Protein binding 96% 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 elimination Not Available
Half life The mean elimination half-life of riluzole is 12 hours (CV=35%) after repeated doses.
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • Impax laboratories inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Rilutek 50 mg tablet 18.77 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5527814 1993-06-18 2013-06-18
Canada 2151604 2005-09-20 2013-12-10
Canada 2117466 2000-01-25 2012-10-22
Properties
State solid
Experimental Properties
Property Value Source
melting point 119 °C Not Available
logP 2.3 Not Available
Predicted Properties
Property Value Source
water solubility 3.95e-02 g/l ALOGPS
logP 2.83 ALOGPS
logP 3.4 ChemAxon
logS -3.8 ALOGPS
pKa (strongest acidic) 16.44 ChemAxon
pKa (strongest basic) 4.57 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 48.14 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 44.37 ChemAxon
polarizability 18.59 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00775 Link_out
KEGG Compound C07937 Link_out
PubChem Compound 5070 Link_out
PubChem Substance 46508094 Link_out
ChemSpider 4892 Link_out
BindingDB 30705 Link_out
Therapeutic Targets Database DAP000527 Link_out
PharmGKB PA451251 Link_out
IUPHAR 2326 Link_out
Guide to Pharmacology 2326 Link_out
Drug Product Database 2242763 Link_out
RxList http://www.rxlist.com/cgi/generic3/riluzole.htm Link_out
Drugs.com http://www.drugs.com/cdi/riluzole.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Riluzole Link_out
ATC Codes
  • N07XX02
AHFS Codes
  • 28:92.00
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Take on an empty stomach 1 hour before or 2 hours after meals.
Targets

1. Sodium channel protein type 5 subunit alpha

Pharmacological action: yes
Actions: inhibitor

This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential in the electrocardiogram

Organism class: human
UniProt ID: Q14524 Link_out
Gene: SCN5A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inducer

Sodium-independent, high-affinity exchange of anionic amino acids with high specificity for anionic form of cystine and glutamate

Organism class: human
UniProt ID: Q9UPY5 Link_out
Gene: SLC7A11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P04798 Link_out
Gene: CYP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123

UniProt ID: Q9UNQ0 Link_out
Gene: ABCG2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19