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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
Octanedioic acid hydroxyamide phenylamide
SAHA
SHH
Suberanilohydroxamic acid
Suberoylanilide hydroxamic acid
Vorinostatum
Zolinza
External Identifiers
  • MK0683
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Zolinzacapsule100 mg/1oralMerck Sharp & Dohme Corp.2006-10-06Not applicableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Zolinzacapsule100 mgoralMerck Canada Inc2009-06-29Not applicableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot 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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as n-arylamides. These are organic compounds that contain a carboxamide group that is N-linked to a aryl group. They have the generic structure RC(=O)N(R')H, R = organyl group and R'= aryl group.
KingdomOrganic compounds
Super ClassOrganonitrogen compounds
ClassN-arylamides
Sub ClassNot Available
Direct ParentN-arylamides
Alternative Parents
Substituents
  • N-arylamide
  • Anilide
  • Fatty acyl
  • Benzenoid
  • Fatty amide
  • Monocyclic benzene moiety
  • Secondary carboxylic acid amide
  • Hydroxamic acid
  • Carboxamide group
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
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
Not Available
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
PropertyValueProbability
Human Intestinal Absorption+0.8458
Blood Brain Barrier+0.9861
Caco-2 permeable-0.8957
P-glycoprotein substrateNon-substrate0.6928
P-glycoprotein inhibitor INon-inhibitor0.8741
P-glycoprotein inhibitor IINon-inhibitor0.9317
Renal organic cation transporterNon-inhibitor0.9169
CYP450 2C9 substrateNon-substrate0.8437
CYP450 2D6 substrateNon-substrate0.8345
CYP450 3A4 substrateNon-substrate0.6536
CYP450 1A2 substrateNon-inhibitor0.824
CYP450 2C9 inhibitorNon-inhibitor0.9084
CYP450 2D6 inhibitorNon-inhibitor0.9204
CYP450 2C19 inhibitorNon-inhibitor0.88
CYP450 3A4 inhibitorNon-inhibitor0.9347
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9336
Ames testAMES toxic0.7891
CarcinogenicityNon-carcinogens0.7278
BiodegradationNot ready biodegradable0.8297
Rat acute toxicity1.9954 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9603
hERG inhibition (predictor II)Non-inhibitor0.8674
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Capsuleoral100 mg/1
Capsuleoral100 mg
Prices
Unit descriptionCostUnit
Zolinza 100 mg capsule83.11USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada21206192006-11-212012-10-05
United States60873671994-10-042011-10-04
United States74562192006-11-142026-11-14
Properties
StateSolid
Experimental Properties
PropertyValueSource
pKa9.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0716 mg/mLALOGPS
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 Area78.43 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity73.81 m3·mol-1ChemAxon
Polarizability28.39 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
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 References
  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
ATC CodesL01XX38
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AcenocoumarolVorinostat may increase the anticoagulant activities of Acenocoumarol.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Vorinostat.
AlogliptinThe therapeutic efficacy of Alogliptin can be decreased when used in combination with Vorinostat.
CanagliflozinThe therapeutic efficacy of Canagliflozin can be decreased when used in combination with Vorinostat.
ChlorpropamideThe therapeutic efficacy of Chlorpropamide can be decreased when used in combination with Vorinostat.
CitalopramVorinostat may increase the QTc-prolonging activities of Citalopram.
ClozapineThe risk or severity of adverse effects can be increased when Vorinostat is combined with Clozapine.
DicoumarolVorinostat may increase the anticoagulant activities of Dicoumarol.
DofetilideVorinostat may increase the QTc-prolonging activities of Dofetilide.
GliclazideThe therapeutic efficacy of Gliclazide can be decreased when used in combination with Vorinostat.
GlimepirideThe therapeutic efficacy of Glimepiride can be decreased when used in combination with Vorinostat.
GliquidoneThe therapeutic efficacy of Gliquidone can be decreased when used in combination with Vorinostat.
GlyburideThe therapeutic efficacy of Glyburide can be decreased when used in combination with Vorinostat.
GoserelinVorinostat may increase the QTc-prolonging activities of Goserelin.
Insulin AspartThe therapeutic efficacy of Insulin Aspart can be decreased when used in combination with Vorinostat.
Insulin DetemirThe therapeutic efficacy of Insulin Detemir can be decreased when used in combination with Vorinostat.
Insulin GlargineThe therapeutic efficacy of Insulin Glargine can be decreased when used in combination with Vorinostat.
Insulin GlulisineThe therapeutic efficacy of Insulin Glulisine can be decreased when used in combination with Vorinostat.
Insulin LisproThe therapeutic efficacy of Insulin Lispro can be decreased when used in combination with Vorinostat.
Insulin RegularThe therapeutic efficacy of Insulin Regular can be decreased when used in combination with Vorinostat.
Insulin, isophaneThe therapeutic efficacy of Insulin, isophane can be decreased when used in combination with Vorinostat.
LeuprolideVorinostat may increase the QTc-prolonging activities of Leuprolide.
LinagliptinThe therapeutic efficacy of Linagliptin can be decreased when used in combination with Vorinostat.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Vorinostat.
MetforminThe therapeutic efficacy of Metformin can be decreased when used in combination with Vorinostat.
MifepristoneMifepristone may increase the QTc-prolonging activities of Vorinostat.
RepaglinideThe therapeutic efficacy of Repaglinide can be decreased when used in combination with Vorinostat.
SaxagliptinThe therapeutic efficacy of Saxagliptin can be decreased when used in combination with Vorinostat.
TolbutamideThe therapeutic efficacy of Tolbutamide can be decreased when used in combination with Vorinostat.
Valproic AcidValproic Acid may increase the thrombocytopenic activities of Vorinostat.
VildagliptinThe therapeutic efficacy of Vildagliptin can be decreased when used in combination with Vorinostat.
WarfarinVorinostat may increase the anticoagulant activities of Warfarin.
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.

Targets

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
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:18