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Identification
NameLevamisole
Accession NumberDB00848  (APRD01067)
TypeSmall Molecule
GroupsWithdrawn
Description

An antihelminthic drug that has been tried experimentally in rheumatic disorders where it apparently restores the immune response by increasing macrophage chemotaxis and T-lymphocyte function. Paradoxically, this immune enhancement appears to be beneficial in rheumatoid arthritis where dermatitis, leukopenia, and thrombocytopenia, and nausea and vomiting have been reported as side effects. (From Smith and Reynard, Textbook of Pharmacology, 1991, p435-6). Levamisole was withdrawn from the US and Canadian markets in 2000 and 2003, respectively, due to the risk of serious side effects and the availability of more effective replacement medications. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
LevamisolSpanishINN
LevamisolumLatinINN
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
ErgamisolJanssen
KetraxAstraZeneca
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Levamisole hydrochloride
Thumb
  • InChI Key: LAZPBGZRMVRFKY-HNCPQSOCSA-N
  • Monoisotopic Mass: 240.048796823
  • Average Mass: 240.752
DBSALT000822
Categories
CAS number14769-73-4
WeightAverage: 204.291
Monoisotopic: 204.072119084
Chemical FormulaC11H12N2S
InChI KeyHLFSDGLLUJUHTE-SNVBAGLBSA-N
InChI
InChI=1S/C11H12N2S/c1-2-4-9(5-3-1)10-8-13-6-7-14-11(13)12-10/h1-5,10H,6-8H2/t10-/m1/s1
IUPAC Name
(6S)-6-phenyl-2H,3H,5H,6H-imidazo[2,1-b][1,3]thiazole
SMILES
C1CN2C[C@@H](N=C2S1)C1=CC=CC=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as imidazothiazoles. These are organic polycyclic compounds containing an imidazole ring fused to a thiazole ring. Imidazole is 5-membered ring consisting of three carbon atoms, and two nitrogen centers at the 1- and 3-positions. Thiazole is a 6-membered ring that contains both sulfur and nitrogen.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassImidazothiazoles
Sub ClassNot Available
Direct ParentImidazothiazoles
Alternative Parents
Substituents
  • Imidazothiazole
  • Benzenoid
  • Monocyclic benzene moiety
  • Thiazolidine
  • 2-imidazoline
  • Tertiary amine
  • Isothiourea
  • Azacycle
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Carboximidamide
  • Thioether
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
  • 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole (CHEBI:6432 )
Pharmacology
IndicationFor adjuvant treatment in combination with fluorouracil after surgical resection in patients with Dukes' stage C colon cancer. Also used to treat malignant melanoma and head/neck cancer. Levamisole was originally used as an antihelminthic to treat worm infestations in both humans and animals.
PharmacodynamicsLevamisole is a synthetic imidazothiazole derivative that has been widely used in treatment of worm infestations in both humans and animals. As an anthelmintic, it probably works by targeting the nematode nicotinergic acetylcholine receptor. As an immunomodulator, it appears that Levamisole is an immunostimulant which has been shown to increase NK cells and activated T-cells in patients receiving this adjuvantly along with 5FU for Stage III colon cancer.
Mechanism of actionThe mechanism of action of levamisole as an antiparasitic agent appears to be tied to its agnositic activity towards the L-subtype nicotinic acetylcholine receptors in nematode muscles. This agonistic action reduces the capacity of the males to control their reproductive muscles and limits their ability to copulate. The mechanism of action of Levamisole as an anticancer drug in combination with fluorouracil is unknown. The effects of levamisole on the immune system are complex. The drug appears to restore depressed immune function rather than to stimulate response to above-normal levels. Levamisole can stimulate formation of antibodies to various antigens, enhance T-cell responses by stimulating T-cell activation and proliferation, potentiate monocyte and macrophage functions including phagocytosis and chemotaxis, and increase neutrophil mobility, adherence, and chemotaxis.
AbsorptionLevamisole is rapidly absorbed (2 hours) from the gastrointestinal tract.
Volume of distributionNot Available
Protein binding20-25%
Metabolism

Primarily hepatic (extensive) with both active and inactive metabolites.

Route of eliminationNot Available
Half life4.4-5.6 hours (biphasic)
ClearanceNot Available
ToxicityLD50 = 40 mg/kg (Pigs, subcutaneous); LD50 = 180 mg/kg (rat, oral)
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9868
Blood Brain Barrier+0.9513
Caco-2 permeable+0.5286
P-glycoprotein substrateSubstrate0.6429
P-glycoprotein inhibitor INon-inhibitor0.7329
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterInhibitor0.728
CYP450 2C9 substrateNon-substrate0.8531
CYP450 2D6 substrateNon-substrate0.5639
CYP450 3A4 substrateNon-substrate0.7161
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 substrateNon-inhibitor0.9071
CYP450 2D6 substrateInhibitor0.8026
CYP450 2C19 substrateNon-inhibitor0.9026
CYP450 3A4 substrateNon-inhibitor0.9238
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.837
Ames testNon AMES toxic0.6514
CarcinogenicityNon-carcinogens0.935
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6601 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7472
hERG inhibition (predictor II)Non-inhibitor0.8734
Pharmacoeconomics
Manufacturers
  • Janssen pharmaceutica products lp
Packagers
  • Professional Co.
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Levamisole hcl powder7.5USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point227-227.5 U.S. Patents 3,274,209; 3,364,112; 3,463,786; 3,579,530 and 3,646,051.
water solubility210 mg/mLNot Available
logP1.84BIOBYTE (1995)
Predicted Properties
PropertyValueSource
Water Solubility1.44 mg/mLALOGPS
logP2.2ALOGPS
logP2.36ChemAxon
logS-2.1ALOGPS
pKa (Strongest Basic)6.98ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area15.6 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity60.08 m3·mol-1ChemAxon
Polarizability22.35 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

U.S. Patents 3,274,209; 3,364,112; 3,463,786; 3,579,530 and 3,646,051.

US3274209
General Reference
  1. Grishchenko SV, Lavrukhina LA, Ketiladze ES, Krylov VF, Ershov FI: [Results of combined therapy using levamisole for patients with influenza complicated by pneumonia] Vopr Virusol. 1984 Mar-Apr;29(2):175-9. Pubmed
  2. Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. British Association for Paediatric Nephrology. Lancet. 1991 Jun 29;337(8757):1555-7. Pubmed
  3. Van Belle H: Alkaline phosphatase. I. Kinetics and inhibition by levamisole of purified isoenzymes from humans. Clin Chem. 1976 Jul;22(7):972-6. Pubmed
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (75.3 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Neuronal acetylcholine receptor subunit alpha-3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Neuronal acetylcholine receptor subunit alpha-3 P32297 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. Culetto E, Baylis HA, Richmond JE, Jones AK, Fleming JT, Squire MD, Lewis JA, Sattelle DB: The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit. J Biol Chem. 2004 Oct 8;279(41):42476-83. Epub 2004 Jul 27. Pubmed
  4. Rayes D, Flamini M, Hernando G, Bouzat C: Activation of single nicotinic receptor channels from Caenorhabditis elegans muscle. Mol Pharmacol. 2007 May;71(5):1407-15. Epub 2007 Feb 21. Pubmed
  5. Parker S, Peterkin HS, Baylis HA: Muscular dystrophy associated mutations in caveolin-1 induce neurotransmission and locomotion defects in Caenorhabditis elegans. Invert Neurosci. 2007 Sep;7(3):157-64. Epub 2007 Jul 13. Pubmed
  6. Hu Y, Xiao SH, Aroian RV: The new anthelmintic tribendimidine is an L-type (levamisole and pyrantel) nicotinic acetylcholine receptor agonist. PLoS Negl Trop Dis. 2009 Aug 11;3(8):e499. Pubmed
  7. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed

2. Alkaline phosphatase, placental-like

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Alkaline phosphatase, placental-like P10696 Details

References:

  1. Chang YL, Stanford CM, Keller JC: Calcium and phosphate supplementation promotes bone cell mineralization: implications for hydroxyapatite (HA)-enhanced bone formation. J Biomed Mater Res. 2000 Nov;52(2):270-8. Pubmed
  2. Funk CJ: Alkaline phosphatase activity in whitefly salivary glands and saliva. Arch Insect Biochem Physiol. 2001 Apr;46(4):165-74. Pubmed
  3. de Aguiar Matos JA, Borges FP, Tasca T, Bogo MR, De Carli GA, da Graca Fauth M, Dias RD, Bonan CD: Characterisation of an ATP diphosphohydrolase (Apyrase, EC 3.6.1.5) activity in Trichomonas vaginalis. Int J Parasitol. 2001 Jun;31(8):770-5. Pubmed
  4. McDougall K, Plumb C, King WA, Hahnel A: Inhibitor profiles of alkaline phosphatases in bovine preattachment embryos and adult tissues. J Histochem Cytochem. 2002 Mar;50(3):415-22. Pubmed
  5. Soory M, Suchak A: Effects of alkaline phosphatase and its inhibitor levamisole on the modulation of androgen metabolism by nicotine and minocycline in human gingival and oral periosteal fibroblasts. Arch Oral Biol. 2003 Jan;48(1):69-76. Pubmed
  6. Mota A, Silva P, Neves D, Lemos C, Calhau C, Torres D, Martel F, Fraga H, Ribeiro L, Alcada MN, Pinho MJ, Negrao MR, Pedrosa R, Guerreiro S, Guimaraes JT, Azevedo I, Martins MJ: Characterization of rat heart alkaline phosphatase isoenzymes and modulation of activity. Braz J Med Biol Res. 2008 Jul;41(7):600-9. Pubmed

3. Acetylcholine receptor subunit alpha-type unc-38

Kind: protein

Organism: Caenorhabditis elegans

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Acetylcholine receptor subunit alpha-type unc-38 Q23022 Details

References:

  1. Culetto E, Baylis HA, Richmond JE, Jones AK, Fleming JT, Squire MD, Lewis JA, Sattelle DB: The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit. J Biol Chem. 2004 Oct 8;279(41):42476-83. Epub 2004 Jul 27. Pubmed
  2. Rayes D, Flamini M, Hernando G, Bouzat C: Activation of single nicotinic receptor channels from Caenorhabditis elegans muscle. Mol Pharmacol. 2007 May;71(5):1407-15. Epub 2007 Feb 21. Pubmed

4. Acetylcholine receptor subunit alpha-type unc-63

Kind: protein

Organism: Caenorhabditis elegans

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Acetylcholine receptor subunit alpha-type unc-63 Q9N587 Details

References:

  1. Culetto E, Baylis HA, Richmond JE, Jones AK, Fleming JT, Squire MD, Lewis JA, Sattelle DB: The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit. J Biol Chem. 2004 Oct 8;279(41):42476-83. Epub 2004 Jul 27. Pubmed
  2. Rayes D, Flamini M, Hernando G, Bouzat C: Activation of single nicotinic receptor channels from Caenorhabditis elegans muscle. Mol Pharmacol. 2007 May;71(5):1407-15. Epub 2007 Feb 21. Pubmed

5. Acetylcholine receptor subunit beta-type lev-1

Kind: protein

Organism: Caenorhabditis elegans

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Acetylcholine receptor subunit beta-type lev-1 Q27218 Details

References:

  1. Culetto E, Baylis HA, Richmond JE, Jones AK, Fleming JT, Squire MD, Lewis JA, Sattelle DB: The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit. J Biol Chem. 2004 Oct 8;279(41):42476-83. Epub 2004 Jul 27. Pubmed
  2. Rayes D, Flamini M, Hernando G, Bouzat C: Activation of single nicotinic receptor channels from Caenorhabditis elegans muscle. Mol Pharmacol. 2007 May;71(5):1407-15. Epub 2007 Feb 21. Pubmed

6. Acetylcholine receptor subunit beta-type unc-29

Kind: protein

Organism: Caenorhabditis elegans

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Acetylcholine receptor subunit beta-type unc-29 P48181 Details

References:

  1. Culetto E, Baylis HA, Richmond JE, Jones AK, Fleming JT, Squire MD, Lewis JA, Sattelle DB: The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit. J Biol Chem. 2004 Oct 8;279(41):42476-83. Epub 2004 Jul 27. Pubmed
  2. Rayes D, Flamini M, Hernando G, Bouzat C: Activation of single nicotinic receptor channels from Caenorhabditis elegans muscle. Mol Pharmacol. 2007 May;71(5):1407-15. Epub 2007 Feb 21. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on May 05, 2014 12:45