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targets (5) enzymes (8)
for drugs
Identification
Name Thalidomide
Accession Number DB01041 (APRD01251)
Type small molecule
Groups approved, withdrawn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A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects.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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • alpha-phthalimidoglutarimide
  • N-Phthalimidoglutamic acid imide
  • N-Phthaloylglutamimide
  • N-Phthalylglutamic acid imide
  • thalidomide
  • Thalidomine USP26
Brand names
  • Algosediv
  • Asidon 3
  • Asmadion
  • Asmaval
  • Bonbrain
  • Bonbrrin
  • Calmore
  • Calmorex
  • Contergan
  • Corronarobetin
  • Distaval
  • Distaxal
  • Distoval
  • Ectiluran
  • Enterosediv
  • Gastrinide
  • Glupan
  • Glutanon
  • Grippex
  • Hippuzon
  • Imida-Lab
  • Imidan
  • Imidene
  • Isomin
  • Kedavon
  • Kevadon
  • Lulamin
  • Neaufatin
  • Neo
  • Neosedyn
  • Neosydyn
  • Nerosedyn
  • Neufatin
  • Neurodyn
  • Neurosedin
  • Neurosedym
  • Neurosedyn
  • Nevrodyn
  • Nibrol
  • Noctosediv
  • Noxodyn
  • Pangul
  • Pantosediv
  • Poly-Giron
  • Polygripan
  • Predni-Sediv
  • Pro-ban M
  • Profarmil
  • Psycholiquid
  • Psychotablets
  • Quetimid
  • Quietoplex
  • Sandormin
  • Sedalis
  • Sedalis sedi-lab
  • Sedimide
  • Sedin
  • Sedisperil
  • Sedoval
  • Shin-naito S
  • Shinnibrol
  • Sleepan
  • Slipro
  • Softenil
  • Softenon
  • Talargan
  • Talimol
  • Talismol
  • Telagan
  • Telargan
  • Telargean
  • Tensival
  • Thalin
  • Thalinette
  • Thalomid
  • Theophilcholine
  • Valgis
  • Valgraine
  • Yodomin
Brand name mixtures Not Available
Categories
  • Immunosuppressive Agents
  • Leprostatic Agents
  • Teratogens
  • Angiogenesis Inhibitors
CAS number 50-35-1
Weight Average: 258.2295
Monoisotopic: 258.064056818
Chemical Formula C13H10N2O4
InChI Key InChIKey=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)
Plain Text
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=C1C=CC=C2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Delta Lactams
  • Piperidines
  • Indoles and Indole Derivatives
  • Benzoyl Derivatives
  • Benzamides
Substructures
  • Delta Lactams
  • Carboxylic Acids and Derivatives
  • Amino Ketones
  • Benzene and Derivatives
  • Piperidines
  • Indoles and Indole Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Benzoyl Derivatives
  • Benzamides
  • Pyrrolines
Pharmacology
Indication For 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.
Pharmacodynamics Thalidomide 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 action In 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.
Absorption The 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 distribution Not Available
Protein binding 55% 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.

Enzyme Metabolite Reaction Km Vmax
Prostaglandin G/H synthase 1 ring opening
Prostaglandin G/H synthase 1 ring opening
Cytochrome P450 1A2 Arene oxide
Cytochrome P450 2E1 Arene oxide
Cytochrome P450 2C19 cis, trans-5'-Hydroxythalidomide
Cytochrome P450 2C19 5-Hydroxythalidomide
Cytochrome P450 2C19 Arene oxide
Cytochrome P450 1A1 Arene oxide
Route of elimination Thalidomide itself has less than 0.7% of the dose excreted in the urine as unchanged drug.
Half life The mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing.
Clearance Not Available
Toxicity The 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Celgene corp
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Thalomid 28 50 mg capsule Disp Pack 4372.47 USD disp
Thalomid 200 mg capsule 277.5 USD capsule
Thalomid 150 mg capsule 260.61 USD capsule
Thalomid 100 mg capsule 243.73 USD capsule
Thalomid 50 mg capsule 150.15 USD capsule
Patents
Country Patent Number Approved Expires
United States 7230012 2003-12-09 2023-12-09
United States 6235756 1993-03-01 2013-03-01
Canada 2505964 2009-07-28 2023-11-13
Canada 2157288 2005-11-08 2014-02-24
Properties
State solid
Melting point 270 oC
Experimental Properties
Property Value Source
water solubility 545 mg/L PhysProp
logP 0.3 PhysProp
Predicted Properties
Property Value Source
water solubility 2.55e+00 g/l ALOGPS
logP 0.42 ALOGPS
logP 0.02 ChemAxon Molconvert
logS -2.00 ALOGPS
pKa 16.74 ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 83.55 ChemAxon Molconvert
rotatable bond count 1 ChemAxon Molconvert
refractivity 64.32 ChemAxon Molconvert
polarizability 24.42 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00754 Link_out
KEGG Compound C07910 Link_out
PubChem Compound 5426 Link_out
PubChem Substance 46505665 Link_out
ChemSpider 5233 Link_out
BindingDB 50070114 Link_out
Therapeutic Targets Database DAP000865 Link_out
PharmGKB PA451644 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic2/thalidom.htm Link_out
Drugs.com http://www.drugs.com/cdi/thalidomide.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Thalidomide Link_out
ATC Codes
  • L04AX02
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (179.8 KB)
MSDS show (58.6 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Tumor necrosis factor

Pharmacological action: yes
Actions: inhibitor

Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin 1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation

Organism class: human
UniProt ID: P01375 Link_out
Gene: TNF Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. Nuclear factor NF-kappa-B p105 subunit

Pharmacological action: yes
Actions: antagonist

Appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur posttranslationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. Plays a role in the regulation of apoptosis

Organism class: human
UniProt ID: P19838 Link_out
Gene: NFKB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

3. DNA

Pharmacological action: yes
Actions: intercalation

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

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

4. Fibroblast growth factor receptor 2

Pharmacological action: yes
Actions: antagonist

Receptor for acidic and basic fibroblast growth factors

Organism class: human
UniProt ID: P21802 Link_out
Gene: FGFR2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

5. Prostaglandin G/H synthase 2

Pharmacological action: unknown
Actions: antagonist

May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity

Organism class: human
UniProt ID: P35354 Link_out
Gene: PTGS2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Cytochrome P450 2C19

Actions: substrate, inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

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. 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

Actions: substrate

Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

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. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells

UniProt ID: P23219 Link_out
Gene: PTGS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity

UniProt ID: P35354 Link_out
Gene: PTGS2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inducer

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: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

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. 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 November 10, 2010 13:45

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.