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Identification
NameVorinostat
Accession NumberDB02546  (EXPT02902)
Typesmall molecule
Groupsapproved, investigational
Description

Vorinostat (rINN) or suberoylanilide hydroxamic acid (SAHA), is a drug currently under investigation for the treatment of cutaneous T cell lymphoma (CTCL), a type of skin cancer, to be used when the disease persists, gets worse, or comes back during or after treatment with other medicines. It is the first in a new class of agents known as histone deacetylase inhibitors. A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4 – 4.4 months in earlier studies). Further brain tumor trials are planned in which vorinostat will be combined with other drugs. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
Octanedioic acid hydroxyamide phenylamideNot AvailableNot Available
SAHANot AvailableNot Available
SHHNot AvailableNot Available
Suberanilohydroxamic acidNot AvailableNot Available
Suberoylanilide hydroxamic acidNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ZolinzaNot Available
Brand mixturesNot Available
Categories
CAS number149647-78-9
WeightAverage: 264.3202
Monoisotopic: 264.147392516
Chemical FormulaC14H20N2O3
InChI KeyInChIKey=WAEXFXRVDQXREF-UHFFFAOYSA-N
InChI
InChI=1S/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18)
IUPAC Name
N-hydroxy-N'-phenyloctanediamide
SMILES
ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassFatty Amides
SubclassN-acyl Amines
Direct parentN-acyl Amines
Alternative parentsAnilides; Hydroxamic Acids; Secondary Carboxylic Acid Amides; Enolates; Carboxylic Acids; Polyamines
Substituentsacetanilide; benzene; secondary carboxylic acid amide; hydroxamic acid; carboxamide group; carboxylic acid derivative; carboxylic acid; enolate; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the n-acyl amines. These are compounds containing a fatty acid moiety linked to an amine group through an ester linkage.
Pharmacology
IndicationFor the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies.
PharmacodynamicsNot Available
Mechanism of actionVorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50< 86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of histones proteins. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. By inhibiting histone deacetylase, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.
AbsorptionNot Available
Volume of distributionNot Available
Protein binding71%
Metabolism

The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).

SubstrateEnzymesProduct
Vorinostat
    4-anilino-4-oxobutanoic acidDetails
    Route of eliminationIn vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. However, renal excretion does not play a role in the elimination of vorinostat.
    Half life2 hours
    ClearanceNot Available
    ToxicityNot Available
    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 + 0.8458
    Blood Brain Barrier + 0.9861
    Caco-2 permeable - 0.8957
    P-glycoprotein substrate Non-substrate 0.6928
    P-glycoprotein inhibitor I Non-inhibitor 0.8741
    P-glycoprotein inhibitor II Non-inhibitor 0.9317
    Renal organic cation transporter Non-inhibitor 0.9169
    CYP450 2C9 substrate Non-substrate 0.8437
    CYP450 2D6 substrate Non-substrate 0.8345
    CYP450 3A4 substrate Non-substrate 0.6536
    CYP450 1A2 substrate Non-inhibitor 0.824
    CYP450 2C9 substrate Non-inhibitor 0.9084
    CYP450 2D6 substrate Non-inhibitor 0.9204
    CYP450 2C19 substrate Non-inhibitor 0.88
    CYP450 3A4 substrate Non-inhibitor 0.9347
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9336
    Ames test AMES toxic 0.7891
    Carcinogenicity Non-carcinogens 0.7278
    Biodegradation Not ready biodegradable 0.8297
    Rat acute toxicity 1.9954 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9603
    hERG inhibition (predictor II) Non-inhibitor 0.8674
    Pharmacoeconomics
    Manufacturers
    • Merck and co inc
    Packagers
    Dosage forms
    FormRouteStrength
    CapsuleOral
    Prices
    Unit descriptionCostUnit
    Zolinza 100 mg capsule83.11USDcapsule
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States74562192006-11-142026-11-14
    United States60873671994-10-042011-10-04
    Canada21206192006-11-212012-10-05
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    pKa9.2Not Available
    Predicted Properties
    PropertyValueSource
    water solubility7.16e-02 g/lALOGPS
    logP1.88ALOGPS
    logP2ChemAxon
    logS-3.6ALOGPS
    pKa (strongest acidic)8.91ChemAxon
    pKa (strongest basic)-3.5ChemAxon
    physiological charge0ChemAxon
    hydrogen acceptor count3ChemAxon
    hydrogen donor count3ChemAxon
    polar surface area78.43ChemAxon
    rotatable bond count8ChemAxon
    refractivity73.81ChemAxon
    polarizability28.39ChemAxon
    number of rings1ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Vinayak G. Gore, Madhukar S. Patil, Rahul A. Bhalerao, Hemant M. Mande, Sandeep G. Mekde, “PROCESS FOR THE PREPARATION OF VORINOSTAT.” U.S. Patent US20110263712, issued October 27, 2011.

    US20110263712
    General Reference
    1. Munshi A, Tanaka T, Hobbs ML, Tucker SL, Richon VM, Meyn RE: Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther. 2006 Aug;5(8):1967-74. Pubmed
    External Links
    ResourceLink
    PubChem Compound5311
    PubChem Substance46508989
    ChemSpider5120
    BindingDB19149
    Therapeutic Targets DatabaseDAP001082
    PharmGKBPA164748224
    HETSHH
    RxListhttp://www.rxlist.com/cgi/generic/zolinza.htm
    Drugs.comhttp://www.drugs.com/cdi/vorinostat.html
    WikipediaVorinostat
    ATC CodesL01XX38
    AHFS CodesNot Available
    PDB Entries
    FDA labelNot Available
    MSDSNot Available
    Interactions
    Drug Interactions
    Drug
    AbarelixAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    AmiodaroneAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    AmitriptylineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    AmoxapineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ApomorphineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    Arsenic trioxideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
    AsenapineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    AzithromycinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ChlorpromazineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    CisaprideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ClarithromycinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ClomipramineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    DasatinibAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    DesipramineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    DisopyramideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    DofetilideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    DolasetronAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    DomperidoneAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    DoxepinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    DronedaroneAdditive QTc prolongation may occur. Concomitant therapy is contraindicated.
    DroperidolAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ErythromycinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    FlecainideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    FluconazoleAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    FluoxetineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    FlupentixolAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    FoscarnetAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    GatifloxacinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    HalofantrineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    HaloperidolAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    IbutilideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ImipramineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    IndapamideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    IsradipineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    LapatinibAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    LevofloxacinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    LoxapineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
    MaprotilineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    MefloquineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    MesoridazineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    MethadoneAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    MethotrimeprazineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    MoxifloxacinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    NilotinibAdditive QTc prolongation may occur. Concomitant therapy should be avoided.
    NorfloxacinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    NortriptylineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    OctreotideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    PentamidineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    PerflutrenAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    PimozideAdditive QTc prolongation may occur. Concomitant therapy is contraindicated.
    ProbucolAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ProcainamideAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    PropafenoneAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ProtriptylineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    QuetiapineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    QuinidineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    QuinineAdditive QTc prolongation may occur. Concomitant therapy should be avoided.
    RanolazineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    RisperidoneAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    SotalolAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    SparfloxacinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    SunitinibAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    TacrolimusAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    TelithromycinAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    TetrabenazineAdditive QTc prolongation may occur. Concomitant therapy should be avoided.
    ThioridazineAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ThiothixeneAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ToremifeneAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
    TrimipramineAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    VoriconazoleAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
    ZuclopenthixolAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    Zuclopenthixol acetateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    Zuclopenthixol decanoateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    Food Interactions
    • Oral administration with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted state.

    1. Histone deacetylase 1

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Histone deacetylase 1 Q13547 Details

    References:

    1. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed
    2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

    2. Histone deacetylase 2

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Histone deacetylase 2 Q92769 Details

    References:

    1. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed

    3. Histone deacetylase 3

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Histone deacetylase 3 O15379 Details

    References:

    1. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed

    4. Histone deacetylase 6

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Histone deacetylase 6 Q9UBN7 Details

    References:

    1. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed

    5. Histone deacetylase 8

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Components

    Name UniProt ID Details
    Histone deacetylase 8 Q9BY41 Details

    6. Acetoin utilization protein

    Kind: protein

    Organism: Aquifex aeolicus (strain VF5)

    Pharmacological action: unknown

    Components

    Name UniProt ID Details
    Acetoin utilization protein O67135 Details
    Comments
    Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:18