3-(4-amino-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione

• ChemBase ID: 363
• Molecular Formular: C13H13N3O3
• Molecular Mass: 259.26062
• Monoisotopic Mass: 259.09569129
• SMILES: O=C1N(C2CCC(=O)NC2=O)Cc2c1cccc2N
• Canonical SMILES: O=C1CCC(C(=O)N1)N1Cc2c(C1=O)cccc2N
• 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)
• InChIKey: GOTYRUGSSMKFNF-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 3-(4-amino-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione
• IUPAC Traditional name: lenalidomide; 3-(4-amino-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione
• Brand Name: Revimid; Revlimid (Celgene); Revlimid
• Synonyms: CDC 501; CC-5013; IMiD3; lenalidomide; Lenalidomide; Revlimid; 3-(4-Amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione; 1-Oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; (3S)-3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione; Revimid; Lenalidomide; 3-(4-AMino-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Database IDs

• CAS Number: 191732-72-6
• MDL Number: MFCD22207056; MFCD18064659
• PubChem SID: 160963826; 46505725
• PubChem CID: 216326

CALCULATED PROPERTIES

JChem

• Acid pKa: 11.611916
• H Acceptors: 4
• H Donor: 2
• LogD (pH = 5.5): -0.70813346
• LogD (pH = 7.4): -0.70788205
• Log P: -0.7078522
• Molar Refractivity: 68.2981 cm^3
• Polarizability: 25.243994 Å^3
• Polar Surface Area: 92.5 Å^2
• Rotatable Bonds: 1
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: -0.43
• LOG S: -2.05
• Solubility (Water): 2.33e+00 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; Soluble 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.
• Apperance: Tan Solid
• Melting Point: 260-263°C (dec.)
• Hydrophobicity(logP): -0.4

Safety Information

• Storage Condition: -20°C; -20°C Freezer
• Storage Warning: IRRITANT
• TSCA Listed: false

Pharmacology Properties

• Target: TNF-alpha
• Mechanism of Action: Inhibits the expression of cyclooxygenase-2 (COX-2); Interfering with the immune system and angiogenesis

Product Information

• Purity: 95+%; 98%
• Salt Data: Free Base
• Application(s): Used against multiple myeloma and myelodysplastic syndromes

DETAILS

DrugBank - DB00480

• Drug Groups: approved; investigational
• 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]
• Indication: For the treatment of patients with transfusion-dependent anemia due to low- or intermediate- risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
• Pharmacology: Lenalidomide, 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.
• Toxicity: The 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
• Biotransformation: The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. The process exceeds the glomerular filtration rate and therefore is partially or entirely active.
• Absorption: Rapidly 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 (C_max) by 36%. The pharmacokinetic disposition of lenalidomide is linear.
• Half Life: 3 hours
• Protein Binding: 30%
• Elimination: In healthy volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion.
• References: 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] ; 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] ; Anderson KC: Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Semin Hematol. 2005 Oct;42(4 Suppl 4):S3-8. [Pubmed]
• External Links: Wikipedia; Drugs.com

Selleck Chemicals - S1029

Research Area

• Description: Cancer,Myelofibrosis, Mantle cell lymphoma

Biological Activity

• Description: Lenalidomide (Revlimid, CC-5013) is a TNF-α secretion inhibitor with IC50 of 13 nM.
• Targets: TNF-α
• IC50: 13 nM ^[1]
• In Vitro: Lenalidomide strongly induces IL-2 and sIL-2R production. Lenalidomide-induced tyrosine phosphorylation of CD28 on T cells is followed by a down-stream activation of NF-κB. ^[2] Lenalidomide and pomalidomide inhibits autoubiquitination of CRBN in HEK293 T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplifies pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for Lenalidomide resistance in H929 myeloma cell lines is accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and Lenalidomide, CRBN protein is undetectable. ^[3] Lenalidomide prevents induction of defects by down-regulating tumor cell inhibitory molecule expression. Lenalidomide prevents induction of tumor-induced T cell lytic synapse dysfunction. Lenalidomide treatment blocks CLL cell-induced T cell actin synapse dysfunction, mimicks antibody blockade, and down-regulates expression of CLL inhibitory ligands and their receptors on T cells. Lenalidomide treatment prevents tumor-induced immune suppression in FL, DLBCL, HL, MM, SCC, and OC and down-regulates immunosuppressive ligand expression on all tumor cells examined. CTL killing function significantly increases following antibody blockade of CLL inhibitory ligands or Lenalidomide treatment compared to control treatments. Treatment of autologous CLL-T cell co-cultures with Lenalidomide reverses impaired CD8^+ T cell lytic synapse formation and granzyme B trafficking. ^[4]
• In Vivo: The induction of angiogenesis by bFGF is significantly inhibited by oral treatment of Lenalidomide in a dose-dependent manner. Lenalidomide significantly decreases the percentage of vascularized area from 5.16% (control group) to 2.58% (50 mg/kg). Lenalidomide significantly reduces the calculated total MVL from 21.07 (control) to 8.11 (50 mg/kg). Lenalidomide significantly inhibites HUVEC migration through the fibronectin-coated membranes towards 0.1 ng/mL of bFGF at 100 μM, 1 ng/mL of VEGF at concentrations of 10 μM and 100 μM. ^[5]
• Clinical Trials: Lenalidomide has entered in a Phase II clinical trial in the treatment of chronic lymphocytic leukemia.

Combination Therapy

• Description: Lenalidomide plus Dexamethasone displays very synergistic results with combination index less than 0.1. ^[6] At 0.01 μM (in DU145 cells) and 1 μM (in PC3 cells) Lenalidomide reduces the mean IC50 for Docetaxel by 42% and 36% respectively. In PC3 cells, 1 μM Lenalidomide significantly enhances the apoptotic activity of Docetaxel. ^[7] Lenalidomide reveals synergistic effect in vitro with Bortezomib in co-culture system associating the MCL cell line Jeko-1 to the dendritic-like cells BDCM, by modifying the secretion pattern of these latest. ^[8] Treated with a combination of Lenalidomide and Docetaxel after the tumors has reached 160?mm^2, the tumor growth rate is significantly reduced, and animal survival (as determined by the length of time taken for tumors to reach 15?cm^3) is increased from 48 days to 59 days. ^[9]

Protocol

• Protocol: Kinase Assay ^[1]
• Assay for inhibition of TNF synthesis by human PBMCs: Human PBMCs from normal donors are obtained by Ficoll?Hypaque density centrifugation. Cells (10^6 cells/mL) are cultured in RPMI supplemented with 10 AB+ serum, 2 mM l-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin. Lenalidomide is dissolved in DMSO at 20 mg/mL; further dilution is done with culture medium. The final DMSO concentration in all assays including the controls is 0.25%. Lenalidomide is added to cells 1 hour prior to the addition of LPS. PBMCs (10^6 cells/mL) are stimulated with 1 μg/mL of LPS from Salmonella minnesota R595. Cells, in triplicate, are incubated with LPS for 18?20 hours at 37 °C in 5% CO₂. Supernatants are then harvested and assayed for cytokine levels. In some experiments, supernatants are kept frozen at ?70 °C until use. Cell viability is assayed by Trypan blue exclusion dye method. The concentration of TNFα in the culture supernatants is determined by ELISA. Lenalidomide is assayed in a minimum of three separate experiments. Percent inhibition is determined as 100 × [1 ? (cytokine(experimental)/cytokine(control))].
• Protocol: Animal Study ^[5]
• Animal Models: Adult male Sprague-Dawley rats bearing HUVECs cells
• Formulation: 0.5% DMSO
• Doses: 50 mg/kg and 250 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Muller GW, et al. Bioorg Med Chem Lett, 1999, 9(11), 1625-1630.
• References: [2] Zangari M, et al. Expert Opin Investig Drugs. 2005, 14(11), 1411-1418.
• References: [3] Lopez-Girona A, et al. Leukemia. 2012.
• References: [4] Ramsay AG, et al. Blood, 2012, 120(7), 1412-1421.
• References: [5] Dredge K, et al. Microvasc Res. 2005, 69(1-2), 56-63.
• References: [6] Henry JY, et al. Prostate. 2012, 72(8), 856-867.
• References: [7] Ocio EM, et al. Haematologica, 2010, 95(5), 794-803.
• References: [8] Henry JY, et al. J Clin Oncol, 2010, 28(suppl), Abst e13155.
• References: [9] Moros A, et al. Canc Res, 2012, 72(8, Suppl 1), Abstr #1942.

Toronto Research Chemicals - L328000

Lenalidomide is an immunomodulatory drug; analog of Thalidomide.

REFERENCES

• 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
• 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
• Anderson KC: Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Semin Hematol. 2005 Oct;42(4 Suppl 4):S3-8. Pubmed
• Henry JY, et al. Prostate. 2012, 72(8), 856-867.
• Ocio EM, et al. Haematologica, 2010, 95(5), 794-803.
• Henry JY, et al. J Clin Oncol, 2010, 28(suppl), Abst e13155.
• Moros A, et al. Canc Res, 2012, 72(8, Suppl 1), Abstr #1942.
• Muller GW, et al. Bioorg Med Chem Lett, 1999, 9(11), 1625-1630.
• Zangari M, et al. Expert Opin Investig Drugs. 2005, 14(11), 1411-1418.
• Lopez-Girona A, et al. Leukemia. 2012.
• Ramsay AG, et al. Blood, 2012, 120(7), 1412-1421.
• Dredge K, et al. Microvasc Res. 2005, 69(1-2), 56-63.
• Bartlett, J.B., et al.: Nature Rev., 4, 314 (2004)
• Mitsiades, C.S., et al.: Curr. Opin. Invest. Drugs, 5, 635 (2004)
• List, A., et al.: N. Engl. J. Med., 352, 549 (2004)
• Bennett et al. Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer JAMA 2006;296(21):2558-2560
• 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;352:549-57. PMID 15703420.
• Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Numer SD, Jagannath S, Dhodapkar MV.
• Enhancement of ligand dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood 2006;epub ahead of print. PMID 16569772.
• Anderson KC. Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Semin Hematol 2005;42(4 Suppl 4):S3-8. PMID 16344099.
• Armoiry, X et al. Lenalidomide in the treatment of multiple myeloma: a review J of Clin Pharmacy & Therapeutics 2008;33:219-226
• Vellet, S et al Thalidomide and lenalidomide: mechanism-based potential drug combinations Leukemia and Lymphoma 2008;49(7):1238-1245
• Weber, DM et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America N Engl Med 2007;357(21):2133-2142