You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameThalidomide
Accession NumberDB01041  (APRD01251)
Typesmall molecule
Groupsapproved, investigational, withdrawn
Description

A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
(±)-N-(2,6-dioxo-3-piperidyl)phthalimideNot AvailableNot Available
(±)-thalidomideNot AvailableNot Available
1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolineNot AvailableNot Available
2,6-dioxo-3-phthalimidopiperidineNot AvailableNot Available
N-(2,6-dioxo-3-piperidyl)phthalimideNot AvailableNot Available
N-PhthaloylglutamimideNot AvailableNot Available
N-Phthalylglutamic acid imideNot AvailableNot Available
Pro-ban MNot AvailableBAN
α-(N-phthalimido)glutarimideNot AvailableNot Available
α-N-phthalylglutaramideNot AvailableNot Available
α-phthalimidoglutarimideNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ConterganNot Available
DistavalNot Available
K-17Not Available
SedalisNot Available
SoftenonNot Available
TalimolNot Available
ThaledNot Available
ThalomidNot Available
Brand mixturesNot Available
Categories
CAS number50-35-1
WeightAverage: 258.2295
Monoisotopic: 258.064056818
Chemical FormulaC13H10N2O4
InChI KeyUEJJHQNACJXSKW-UHFFFAOYSA-N
InChI
InChI=1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)
IUPAC Name
2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione
SMILES
O=C1N(C2CCC(=O)NC2=O)C(=O)C2=CC=CC=C12
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassIsoindoles and Derivatives
SubclassIsoindolines
Direct parentIsoindolones
Alternative parentsIsoindoles; Piperidinediones; Delta Lactams; Aminopiperidines; N-substituted Carboxylic Acid Imides; Benzene and Substituted Derivatives; N-unsubstituted Carboxylic Acid Imides; Tertiary Carboxylic Acid Amides; Secondary Carboxylic Acid Amides; Tertiary Amines; Carboxylic Acids; Polyamines; Isoindlines
Substituentspiperidinedione; piperidinone; 3-aminopiperidine; delta-lactam; benzene; piperidine; carboxylic acid imide, n-substituted; tertiary carboxylic acid amide; carboxylic acid imide, n-unsubstituted; carboxylic acid imide; lactam; tertiary amine; carboxamide group; secondary carboxylic acid amide; carboxylic acid derivative; polyamine; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the isoindolones. These are aromatic polycyclic compounds that an isolindole bearing a ketone.
Pharmacology
IndicationFor the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Also for use as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.
PharmacodynamicsThalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: one enantiomer is effective against morning sickness, and the other is teratogenic. The enantiomers are converted to each other in vivo. That is, if a human is given D-thalidomide or L-thalidomide, both isomers can be found in the serum. Hence, administering only one enantiomer will not prevent the teratogenic effect in humans.
Mechanism of actionIn patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-a in patients with ENL, however, it has also been shown to increase plasma TNF-a levels in HIV-seropositive patients. As a cancer treatment, the drug may act as a VEGF inhibitor.
AbsorptionThe absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations (Tmax) ranged from 2.9 to 5.7 hours indicating that thalidomide is slowly absorbed from the gastrointestinal tract.
Volume of distributionNot Available
Protein binding55% and 66% for the (+)R and (−)S enantiomers, respectively.
Metabolism

Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. Thalidomide may be metabolized hepatically by enzymes of the cytochrome P450 enzyme system. The end product of metabolism, phthalic acid, is excreted as a glycine conjugate.

SubstrateEnzymesProduct
Thalidomide
cis, trans-5'-HydroxythalidomideDetails
Thalidomide
5-HydroxythalidomideDetails
Thalidomide
Thalidomide arene oxideDetails
Thalidomide arene oxide
Not Available
5-HydroxythalidomideDetails
5-Hydroxythalidomide
5,6-dihydroxythalidomideDetails
Thalidomide
Not Available
4-phthalimidoglutaramic acidDetails
Thalidomide
Not Available
2-phthalimidoglutaramic acidDetails
2-phthalimidoglutaramic acid
Not Available
2-phthalimidoglutaric acidDetails
4-phthalimidoglutaramic acid
Not Available
2-phthalimidoglutaric acidDetails
Thalidomide
Not Available
alpha-(o-carboxybenzamido)glutarimideDetails
4-phthalimidoglutaramic acid
Not Available
4-(o-carboxybenzamido)glutaramic acidDetails
2-phthalimidoglutaramic acid
Not Available
2-(o-carboxybenzamido)glutaramic acidDetails
alpha-(o-carboxybenzamido)glutarimide
Not Available
2-(o-carboxybenzamido)glutaramic acidDetails
4-(o-carboxybenzamido)glutaramic acid
Not Available
2-(o-carboxybenzamido)glutaric acidDetails
4-(o-carboxybenzamido)glutaramic acid
Not Available
2-(o-carboxybenzamido)glutaric acidDetails
2-(o-carboxybenzamido)glutaramic acid
Not Available
2-(o-carboxybenzamido)glutaric acidDetails
Route of eliminationThalidomide itself has less than 0.7% of the dose excreted in the urine as unchanged drug.
Half lifeThe mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing.
ClearanceNot Available
ToxicityThe R-configuration and the S-configuration are more toxic individually than the racemic mixture. The LD50 could not be established in mice for racemic thalidomide, whereas LD50 values for the R and S configurations are reported to be 0.4 to 0.7 g/kg and 0.5 to 1.5 g/kg, respectively.
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 + 0.9775
Blood Brain Barrier + 0.9382
Caco-2 permeable - 0.5651
P-glycoprotein substrate Substrate 0.5301
P-glycoprotein inhibitor I Non-inhibitor 0.5115
P-glycoprotein inhibitor II Non-inhibitor 0.8951
Renal organic cation transporter Non-inhibitor 0.8179
CYP450 2C9 substrate Non-substrate 0.7904
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.5309
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8682
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.9378
Biodegradation Not ready biodegradable 0.8838
Rat acute toxicity 3.3039 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9769
hERG inhibition (predictor II) Non-inhibitor 0.8735
Pharmacoeconomics
Manufacturers
  • Celgene corp
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Thalomid 28 50 mg capsule Disp Pack4372.47USDdisp
Thalomid 200 mg capsule277.5USDcapsule
Thalomid 150 mg capsule260.61USDcapsule
Thalomid 100 mg capsule243.73USDcapsule
Thalomid 50 mg capsule150.15USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States72300122003-12-092023-12-09
United States62357561993-03-012013-03-01
Canada25059642009-07-282023-11-13
Canada21572882005-11-082014-02-24
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point270 °CPhysProp
water solubility545 mg/L (at 25 °C)BUDAVARI,S ET AL. (1996)
logP0.33HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
water solubility2.55e+00 g/lALOGPS
logP0.42ALOGPS
logP0.016ChemAxon
logS-2ALOGPS
pKa (strongest acidic)11.59ChemAxon
pKa (strongest basic)-6.4ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count1ChemAxon
polar surface area83.55ChemAxon
rotatable bond count1ChemAxon
refractivity64.32ChemAxon
polarizability24.42ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Jamshed Shah, “Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs.” U.S. Patent US20030139451, issued July 24, 2003.

US20030139451
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00754
KEGG CompoundC07910
PubChem Compound5426
PubChem Substance46505665
ChemSpider5233
BindingDB50070114
Therapeutic Targets DatabaseDAP000865
PharmGKBPA451644
RxListhttp://www.rxlist.com/cgi/generic2/thalidom.htm
Drugs.comhttp://www.drugs.com/cdi/thalidomide.html
WikipediaThalidomide
ATC CodesL04AX02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(180 KB)
MSDSshow(58.6 KB)
Interactions
Drug Interactions
Drug
AbataceptThalidomide may increase the adverse effects of Abatacept. Increased risk of serious infection. Concomitant therapy should be avoided.
AmikacinThalidomide increases the renal toxicity of the aminoglycoside
AnakinraThalidomide may increase the adverse effects of Anakinra. Increased risk of serious infection. Concomitant therapy should be avoided.
DexamethasoneIncreased risk of dermatologic adverse effects and venous thromboembolic events (VTE). Consider VTE prophylaxis during concomitant therapy and monitor for adverse dematologic effects.
GentamicinThalidomide increases the renal toxicity of the aminoglycoside
NatalizumabThalidomide may increase the adverse effects of Natalizumab. Concurrent administration should be avoided due to increased risk of infection.
NetilmicinThalidomide increases the renal toxicity of the aminoglycoside
RilonaceptThalidomide may increase the adverse effects of Rilonacept. Increased risk of serious infection. Concomitant therapy should be avoided.
TobramycinThalidomide increases the renal toxicity of the aminoglycoside
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
TriprolidineThe CNS depressants, Triprolidine and Thalidomide, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food InteractionsNot Available

Targets

1. Protein cereblon

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Protein cereblon Q96SW2 Details

References:

  1. Zhu YX, Kortuem KM, Stewart AK: Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013 Apr;54(4):683-7. doi: 10.3109/10428194.2012.728597. Epub 2012 Sep 28. Pubmed

2. Tumor necrosis factor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Tumor necrosis factor P01375 Details

References:

  1. Richardson P, Hideshima T, Anderson K: Thalidomide in multiple myeloma. Biomed Pharmacother. 2002 May;56(3):115-28. Pubmed
  2. Fu LM, Fu-Liu CS: Thalidomide and tuberculosis. Int J Tuberc Lung Dis. 2002 Jul;6(7):569-72. Pubmed
  3. Enomoto N, Takei Y, Hirose M, Ikejima K, Miwa H, Kitamura T, Sato N: Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-alpha production. Gastroenterology. 2002 Jul;123(1):291-300. Pubmed
  4. Rajkumar SV: Thalidomide in the treatment of multiple myeloma. Expert Rev Anticancer Ther. 2001 Jun;1(1):20-8. Pubmed
  5. Vescovo G, Ravara B, Angelini A, Sandri M, Carraro U, Ceconi C, Dalla Libera L: Effect of thalidomide on the skeletal muscle in experimental heart failure. Eur J Heart Fail. 2002 Aug;4(4):455-60. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Turk BE, Jiang H, Liu JO: Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7552-6. Pubmed

3. Nuclear factor NF-kappa-B p105 subunit

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Nuclear factor NF-kappa-B p105 subunit P19838 Details

References:

  1. Yasui K, Kobayashi N, Yamazaki T, Agematsu K: Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. Curr Pharm Des. 2005;11(3):395-401. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

4. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: intercalation

Components

Name UniProt ID Details

References:

  1. Stephens TD, Bunde CJ, Fillmore BJ: Mechanism of action in thalidomide teratogenesis. Biochem Pharmacol. 2000 Jun 15;59(12):1489-99. Pubmed
  2. Shoji A, Kuwahara M, Ozaki H, Sawai H: Modified DNA aptamer that binds the®-isomer of a thalidomide derivative with high enantioselectivity. J Am Chem Soc. 2007 Feb 7;129(5):1456-64. Pubmed
  3. Stephens TD, Fillmore BJ: Hypothesis: thalidomide embryopathy-proposed mechanism of action. Teratology. 2000 Mar;61(3):189-95. Pubmed

5. Fibroblast growth factor receptor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Fibroblast growth factor receptor 2 P21802 Details

References:

  1. Eichholz A, Merchant S, Gaya AM: Anti-angiogenesis therapies: their potential in cancer management. Onco Targets Ther. 2010 Jun 24;3:69-82. Pubmed

6. Prostaglandin G/H synthase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Prostaglandin G/H synthase 2 P35354 Details

References:

  1. Horrobin DF: A low toxicity maintenance regime, using eicosapentaenoic acid and readily available drugs, for mantle cell lymphoma and other malignancies with excess cyclin D1 levels. Med Hypotheses. 2003 May;60(5):615-23. Pubmed
  2. Hada M, Mizutari K: [A case report of metastatic pancreatic cancer that responded remarkably to the combination of thalidomide, celecoxib and irinotecan] Gan To Kagaku Ryoho. 2004 Sep;31(9):1407-10. Pubmed
  3. Payvandi F, Wu L, Haley M, Schafer PH, Zhang LH, Chen RS, Muller GW, Stirling DI: Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. Cell Immunol. 2004 Aug;230(2):81-8. Pubmed
  4. Wiedmann MW, Caca K: Molecularly targeted therapy for gastrointestinal cancer. Curr Cancer Drug Targets. 2005 May;5(3):171-93. Pubmed
  5. Du GJ, Lin HH, Xu QT, Wang MW: Thalidomide inhibits growth of tumors through COX-2 degradation independent of antiangiogenesis. Vascul Pharmacol. 2005 Aug;43(2):112-9. Pubmed
  6. Kim JH, Scialli AR: Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci. 2011 Jul;122(1):1-6. doi: 10.1093/toxsci/kfr088. Epub 2011 Apr 19. Pubmed

7. Nuclear factor kappa-light-chain-enhancer of activated B cells

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details

References:

  1. Kim JH, Scialli AR: Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci. 2011 Jul;122(1):1-6. doi: 10.1093/toxsci/kfr088. Epub 2011 Apr 19. Pubmed

8. alpha1-acid glycoprotein

Kind: protein group

Organism: Human

Pharmacological action: unknown

Actions: binder

Components

Name UniProt ID Details
Alpha-1-acid glycoprotein 1 P02763 Details
Alpha-1-acid glycoprotein 2 P19652 Details

References:

  1. Turk BE, Jiang H, Liu JO: Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7552-6. Pubmed

Enzymes

1. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. 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. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

3. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

5. Prostaglandin G/H synthase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Prostaglandin G/H synthase 1 P23219 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

6. Prostaglandin G/H synthase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Prostaglandin G/H synthase 2 P35354 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

7. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

8. 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. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13