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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Groupsapproved, investigational, withdrawn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A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects.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 KeyInChIKey=UEJJHQNACJXSKW-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
    5-HydroxythalidomideDetails
    5-Hydroxythalidomide
    5,6-dihydroxythalidomideDetails
    Thalidomide
      4-phthalimidoglutaramic acidDetails
      Thalidomide
        2-phthalimidoglutaramic acidDetails
        2-phthalimidoglutaramic acid
          2-phthalimidoglutaric acidDetails
          4-phthalimidoglutaramic acid
            2-phthalimidoglutaric acidDetails
            Thalidomide
              alpha-(o-carboxybenzamido)glutarimideDetails
              4-phthalimidoglutaramic acid
                4-(o-carboxybenzamido)glutaramic acidDetails
                2-phthalimidoglutaramic acid
                  2-(o-carboxybenzamido)glutaramic acidDetails
                  alpha-(o-carboxybenzamido)glutarimide
                    2-(o-carboxybenzamido)glutaramic acidDetails
                    4-(o-carboxybenzamido)glutaramic acid
                      2-(o-carboxybenzamido)glutaric acidDetails
                      4-(o-carboxybenzamido)glutaramic acid
                        2-(o-carboxybenzamido)glutaric acidDetails
                        2-(o-carboxybenzamido)glutaramic acid
                          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

                          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

                          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

                          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
                          Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13