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Identification
NameLenalidomide
Accession NumberDB00480  (APRD01303)
Typesmall molecule
Groupsapproved
Description

Lenalidomide (initially known as CC-5013 and marketed as Revlimid® by Celgene) is a derivative of thalidomide introduced in 2004. It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic modality, but has also shown efficacy in the hematological disorders known as the myelodysplastic syndromes. [Wikipedia] FDA approved on December 27, 2005.

Structure
Thumb
Synonyms
SynonymLanguageCode
CC-5013Not AvailableNot Available
CDC 501Not AvailableNot Available
IMid-1Not AvailableNot Available
IMiD3Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
LadevinaNot Available
Lenangio Not Available
Revlimid Celegene
Brand mixturesNot Available
Categories
CAS number191732-72-6
WeightAverage: 259.2606
Monoisotopic: 259.095691297
Chemical FormulaC13H13N3O3
InChI KeyGOTYRUGSSMKFNF-UHFFFAOYSA-N
InChI
InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)
IUPAC Name
3-(4-amino-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione
SMILES
NC1=CC=CC2=C1CN(C1CCC(=O)NC1=O)C2=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassIsoindoles and Derivatives
SubclassIsoindolines
Direct parentIsoindolones
Alternative parentsIsoindoles; Piperidinediones; Delta Lactams; Aminopiperidines; Anilines; Primary Aromatic Amines; N-unsubstituted Carboxylic Acid Imides; Tertiary Carboxylic Acid Amides; Secondary Carboxylic Acid Amides; Tertiary Amines; Polyamines; Carboxylic Acids; Isoindlines
Substituentspiperidinedione; piperidinone; aniline; 3-aminopiperidine; delta-lactam; piperidine; benzene; primary aromatic amine; tertiary carboxylic acid amide; carboxylic acid imide; carboxylic acid imide, n-unsubstituted; lactam; secondary carboxylic acid amide; tertiary amine; carboxamide group; polyamine; carboxylic acid derivative; carboxylic acid; primary amine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the isoindolones. These are aromatic polycyclic compounds that an isolindole bearing a ketone.
Pharmacology
IndicationLenalidomide is indicated for the treatment of multiple myeloma in combination with dexamethasone. It is also indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate- risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
PharmacodynamicsLenalidomide, a thalidomide analogue, is an immunomodulatory agent possessing immunomodulatory and antiangiogenic properties. Lenalidomide inhibits the secretion of pro-inflammatory cytokines and increases the secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide inhibits cell proliferation with varying effectiveness (IC50s) in some but not all cell lines. Lenalidomide is effective in inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) but is much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and other cell lines without chromosome 5 deletions. Lenalidomide does not prolong the QTc interval.
Mechanism of actionThe mechanism of action of lenalidomide remains to be fully characterized, however it has been demonstrated that lenalidomide inhibits the expression of cyclooxygenase-2 (COX-2), but not COX-1, in vitro. In vivo it induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity
AbsorptionRapidly absorbed following oral administration, with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. Co-administration with food does not alter the extent of absorption (AUC) but does reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of lenalidomide is linear. Accumulation does not occur following multiple doses.
Volume of distributionNot Available
Protein binding30% protein bound.
Metabolism

Lenalidomide undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation. The cytochrome P450 enzyme system is not involved with the metabolism of lenalidomide.

Route of eliminationElimination is primarily renal. When a single oral dose of 25 mg is given healthy subjects, 90% and 4% of the dose is eliminated in urine and feces, respectively. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively.
Half lifeHealthy subjects = 3 hours; Multiple myeloma or MDS patients = 3 - 5 hours.
Clearance

The renal clearance of lenalidomide exceeds the glomerular filtration rate.

ToxicityThe most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.
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 + 0.9958
Blood Brain Barrier + 0.9372
Caco-2 permeable - 0.5981
P-glycoprotein substrate Substrate 0.6845
P-glycoprotein inhibitor I Inhibitor 0.6012
P-glycoprotein inhibitor II Non-inhibitor 0.8927
Renal organic cation transporter Non-inhibitor 0.726
CYP450 2C9 substrate Non-substrate 0.8861
CYP450 2D6 substrate Non-substrate 0.7878
CYP450 3A4 substrate Substrate 0.5855
CYP450 1A2 substrate Non-inhibitor 0.8746
CYP450 2C9 substrate Non-inhibitor 0.8405
CYP450 2D6 substrate Non-inhibitor 0.8806
CYP450 2C19 substrate Non-inhibitor 0.78
CYP450 3A4 substrate Non-inhibitor 0.7469
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.843
Ames test Non AMES toxic 0.8268
Carcinogenicity Non-carcinogens 0.9068
Biodegradation Not ready biodegradable 0.9967
Rat acute toxicity 2.5145 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9803
hERG inhibition (predictor II) Non-inhibitor 0.5098
Pharmacoeconomics
Manufacturers
  • Celgene corp
  • Celgene Corporation
Packagers
Dosage forms
FormRouteStrength
CapsuleOral2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg
Prices
Unit descriptionCostUnit
Revlimid 25 mg capsule411.71USDcapsule
Revlimid 15 mg capsule407.7USDcapsule
Revlimid 10 mg capsule406.05USDcapsule
Revlimid 5 mg capsule388.0USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States74658002006-04-222026-04-22
United States62812301996-07-242016-07-24
Canada24773012009-09-012023-04-13
Canada23429742005-08-162014-02-24
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilitySoluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/mL.Not Available
logP-0.4Not Available
Predicted Properties
PropertyValueSource
water solubility2.33e+00 g/lALOGPS
logP-0.43ALOGPS
logP-0.71ChemAxon
logS-2ALOGPS
pKa (strongest acidic)11.61ChemAxon
pKa (strongest basic)2.31ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count2ChemAxon
polar surface area92.5ChemAxon
rotatable bond count1ChemAxon
refractivity68.3ChemAxon
polarizability25.55ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Surya Narayana Devarakonda, Sesha Reddy Yarraguntla, Vamsi Krishna Mudapaka, Rajasekhar Kadaboina, Veerender Murki, Amarendhar Manda, Venkata Rao Badisa, Naresh Vemula, Rama Seshagiri Rao Pulla, Venu Nalivela, “PREPARATION OF LENALIDOMIDE.” U.S. Patent US20110021567, issued January 27, 2011.

US20110021567
General Reference
  1. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. Pubmed
  2. Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Nimer SD, Jagannath S, Dhodapkar MV: Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006 Jul 15;108(2):618-21. Epub 2006 Mar 28. Pubmed
  3. Anderson KC: Lenalidomide and thalidomide: mechanisms of action—similarities and differences. Semin Hematol. 2005 Oct;42(4 Suppl 4):S3-8. Pubmed
External Links
ResourceLink
KEGG DrugD04687
PubChem Compound216326
PubChem Substance46505725
ChemSpider187515
BindingDB50078323
ChEBI63791
ChEMBLCHEMBL848
Therapeutic Targets DatabaseDAP001255
PharmGKBPA162363968
RxListhttp://www.rxlist.com/revlimid-drug.htm
Drugs.comhttp://www.drugs.com/cdi/lenalidomide.html
WikipediaLenalidomide
ATC CodesL04AX04
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(400 KB)
MSDSshow(225 KB)
Interactions
Drug Interactions
Drug
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions
  • When given with a fatty meal, the extent of absorption is reduced.

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 ligand superfamily member 11

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Tumor necrosis factor ligand superfamily member 11 O14788 Details

References:

  1. Akobeng AK, Stokkers PC: Thalidomide and thalidomide analogues for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD007351. Pubmed
  2. Melchert M, List A: The thalidomide saga. Int J Biochem Cell Biol. 2007;39(7-8):1489-99. Epub 2007 Jan 30. Pubmed

3. Cadherin-5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Cadherin-5 P33151 Details

References:

  1. Lu L, Payvandi F, Wu L, Zhang LH, Hariri RJ, Man HW, Chen RS, Muller GW, Hughes CC, Stirling DI, Schafer PH, Bartlett JB: The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res. 2009 Mar;77(2):78-86. Epub 2008 Sep 4. Pubmed

4. Prostaglandin G/H synthase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: negative modulator

Components

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

References:

  1. 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
  2. Zeldis JB, Schafer PH, Bennett BL, Mercurio F, Stirling DI: Potential new therapeutics for Waldenstrom’s macroglobulinemia. Semin Oncol. 2003 Apr;30(2):275-81. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. FDA label

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:10