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Identification
NameEntacapone
Accession NumberDB00494  (APRD00416)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Entacapone is a selective, reversible catechol-O-methyl transferase (COMT) inhibitor for the treatment of Parkinson’s disease. It is a member of the class of nitrocatechols. When administered concomittantly with levodopa and a decarboxylase inhibitor (e.g., carbidopa), increased and more sustained plasma levodopa concentrations are reached as compared to the administration of levodopa and a decarboxylase inhibitor.

Structure
Thumb
Synonyms
(e)-alpha-Cyano-N,N-diethyl-3,4-dihydroxy-5-nitrocinnamamide
Comtan
Comtess
Entacapona
Entacapone
Entacaponum
N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide
External Identifiers
  • OR 611
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Auro-entacaponetablet200 mgoralAuro Pharma IncNot applicableNot applicableCanada
Comtantablet, film coated200 mg/1oralNovartis Pharmaceuticals Corporation1999-10-19Not applicableUs
Comtantablet, film coated200 mg/1oralCardinal Health2000-01-01Not applicableUs
Comtantablet200 mgoralNovartis Pharmaceuticals Canada Inc2001-06-21Not applicableCanada
Entacaponetablet, film coated200 mg/1oralWockhardt Limited2012-09-30Not applicableUs
Entacaponetablet, film coated200 mg/1oralMylan Institutional Inc.2013-12-12Not applicableUs
Entacaponetablet, film coated200 mg/1oralSun Pharma Global FZE2013-04-01Not applicableUs
Entacaponetablet, film coated200 mg/1oralAvera Mc Kennan Hospital2015-09-23Not applicableUs
Entacaponetablet, film coated200 mg/1oralAv Kare, Inc.2014-06-20Not applicableUs
Entacaponetablet, film coated200 mg/1oralWockhardt USA LLC.2012-09-30Not applicableUs
Entacaponetablet, film coated200 mg/1oralSandoz Inc2014-06-04Not applicableUs
Entacaponetablet, film coated200 mg/1oralWockhardt USA LLC.2012-09-30Not applicableUs
Entacaponetablet, film coated200 mg/1oralMylan Pharmaceuticals Inc.2013-06-26Not applicableUs
Entacaponetablet, film coated200 mg/1oralWockhardt Limited2012-09-30Not applicableUs
Entacaponetablet, film coated200 mg/1oralKAISER FOUNDATION HOSPITALS2014-10-10Not applicableUs
Mylan-entacaponetablet200 mgoralMylan Pharmaceuticals Ulc2012-07-31Not applicableCanada
Sandoz Entacaponetablet200 mgoralSandoz Canada Incorporated2012-03-30Not applicableCanada
Teva-entacaponetablet200 mgoralTeva Canada Limited2012-03-29Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-entacaponetablet200 mgoralApotex IncNot applicableNot applicableCanada
Entacaponetablet, film coated200 mg/1oralSun Pharma Global FZE2012-07-18Not applicableUs
Entacaponetablet, film coated200 mg/1oralAurobindo Pharma Limited2015-06-19Not applicableUs
Entacaponetablet, film coated200 mg/1oralAmerican Health Packaging2016-02-01Not applicableUs
Entacaponetablet, film coated200 mg/1oralWockhardt USA LLC.2012-08-16Not applicableUs
Entacaponetablet, film coated200 mg/1oralWockhardt Limited2012-08-16Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AnxoponeRoot
ComtadeNovartis
ComtessOrion
Brand mixtures
NameLabellerIngredients
Carbidopa, Levodopa and EntacaponeMylan Pharmaceuticals Inc.
Carbidopa, Levodopa, and EntacaponeSandoz Inc
StalevoNovartis Pharmaceuticals Corporation
SaltsNot Available
Categories
UNII4975G9NM6T
CAS number130929-57-6
WeightAverage: 305.286
Monoisotopic: 305.101170605
Chemical FormulaC14H15N3O5
InChI KeyInChIKey=JRURYQJSLYLRLN-BJMVGYQFSA-N
InChI
InChI=1S/C14H15N3O5/c1-3-16(4-2)14(20)10(8-15)5-9-6-11(17(21)22)13(19)12(18)7-9/h5-7,18-19H,3-4H2,1-2H3/b10-5+
IUPAC Name
(2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide
SMILES
CCN(CC)C(=O)C(=C\C1=CC(=C(O)C(O)=C1)[N+]([O-])=O)\C#N
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as hydroxycinnamic acids and derivatives. These are compounds containing an cinnamic acid (or a derivative thereof) where the benzene ring is hydroxylated.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassCinnamic acids and derivatives
Sub ClassHydroxycinnamic acids and derivatives
Direct ParentHydroxycinnamic acids and derivatives
Alternative Parents
Substituents
  • Hydroxycinnamic acid or derivatives
  • Nitrophenol derivative
  • Phenylpropene
  • Nitrobenzene
  • 1,2-diphenol
  • Phenol
  • Benzenoid
  • Monocyclic benzene moiety
  • Tertiary carboxylic acid amide
  • Organic nitro compound
  • Tertiary amine
  • Organic nitrite
  • C-nitro compound
  • Carboxamide group
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Allyl-type 1,3-dipolar organic compound
  • Organic oxoazanium
  • Nitrile
  • Carbonitrile
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organic salt
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Organic zwitterion
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationUsed as an adjunct to levodopa / carbidopa in the symptomatic treatment of patients with idiopathic Parkinson's Disease who experience the signs and symptoms of end-of-dose "wearing-off".
PharmacodynamicsEntacapone is structurally and pharmacologically related to tolcapone, but unlike tolcapone, is not associated with hepatotoxicity. Entacapone is used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa therapy. Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.
Mechanism of actionThe mechanism of action of entacapone is believed to be through its ability to inhibit COMT in peripheral tissues, altering the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to a greater reduction in the manifestations of parkinsonian syndrome.
Related Articles
AbsorptionEntacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.
Volume of distribution
  • 20 L
Protein binding98% (bind to serum albumin)
Metabolism

Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer.

Route of eliminationEntacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug.
Half life0.4-0.7 hour
Clearance
  • 850 mL/min
ToxicitySide effect include increase the occurrence of orthostatic hypotension, severe rhabdomyolysis, dyskinesia, hallucinations, hyperkinesia, hypokinesia, dizziness, fatigu,e gastrointestinal effects including abdominal pain constipation diarrhea nausea
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+0.9185
Blood Brain Barrier-0.9104
Caco-2 permeable-0.5817
P-glycoprotein substrateSubstrate0.64
P-glycoprotein inhibitor INon-inhibitor0.7342
P-glycoprotein inhibitor IINon-inhibitor0.8442
Renal organic cation transporterNon-inhibitor0.9311
CYP450 2C9 substrateNon-substrate0.8406
CYP450 2D6 substrateNon-substrate0.8932
CYP450 3A4 substrateNon-substrate0.5057
CYP450 1A2 substrateNon-inhibitor0.7003
CYP450 2C9 inhibitorNon-inhibitor0.581
CYP450 2D6 inhibitorNon-inhibitor0.8548
CYP450 2C19 inhibitorNon-inhibitor0.6098
CYP450 3A4 inhibitorNon-inhibitor0.5133
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7901
Ames testAMES toxic0.5803
CarcinogenicityNon-carcinogens0.561
BiodegradationNot ready biodegradable0.9457
Rat acute toxicity2.6750 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8608
hERG inhibition (predictor II)Non-inhibitor0.8332
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Orion corp
Packagers
Dosage forms
FormRouteStrength
Tabletoral200 mg
Tablet, film coatedoral200 mg/1
Tabletoral
Tablet, film coatedoral
Prices
Unit descriptionCostUnit
Comtan 200 mg tablet2.96USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA1334967 No1995-03-282012-03-28Canada
CA2342634 No2008-01-292019-09-13Canada
US5135950 No1993-10-312010-10-31Us
US6500867 No2000-06-292020-06-29Us
US6599530 No1998-09-142018-09-14Us
US6797732 No2000-06-292020-06-29Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP2.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0797 mg/mLALOGPS
logP2.5ALOGPS
logP1.63ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)5.68ChemAxon
pKa (Strongest Basic)-0.036ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area130.38 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity80.51 m3·mol-1ChemAxon
Polarizability29.48 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

Pandurang Deshpande, Parven Luthra, Anand Pandey, Dharmesh Dhameliya, “Process for the preparation of (E)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide (entacapone).” U.S. Patent US20060258877, issued November 16, 2006.

US20060258877
General References
  1. Najib J: Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease. Clin Ther. 2001 Jun;23(6):802-32; discussion 771. [PubMed:11440283 ]
  2. Chong BS, Mersfelder TL: Entacapone. Ann Pharmacother. 2000 Sep;34(9):1056-65. [PubMed:10981253 ]
  3. Poewe WH, Deuschl G, Gordin A, Kultalahti ER, Leinonen M: Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand. 2002 Apr;105(4):245-55. [PubMed:11939936 ]
  4. Brooks DJ, Sagar H: Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson's disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry. 2003 Aug;74(8):1071-9. [PubMed:12876237 ]
  5. Forsberg M, Lehtonen M, Heikkinen M, Savolainen J, Jarvinen T, Mannisto PT: Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat. J Pharmacol Exp Ther. 2003 Feb;304(2):498-506. [PubMed:12538800 ]
  6. Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. [PubMed:10882160 ]
External Links
ATC CodesN04BX02
AHFS Codes
  • 28:92.00
PDB EntriesNot Available
FDA labelDownload (52.6 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AldesleukinAldesleukin may increase the orthostatic hypotensive activities of Entacapone.
AripiprazoleThe serum concentration of Aripiprazole can be increased when it is combined with Entacapone.
AzelastineEntacapone may increase the central nervous system depressant (CNS depressant) activities of Azelastine.
BaclofenThe risk or severity of adverse effects can be increased when Baclofen is combined with Entacapone.
BrimonidineBrimonidine may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
BuprenorphineEntacapone may increase the central nervous system depressant (CNS depressant) activities of Buprenorphine.
DiethylstilbestrolThe metabolism of Diethylstilbestrol can be decreased when combined with Entacapone.
DoxylamineDoxylamine may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
DronabinolDronabinol may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
DroperidolDroperidol may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
EthanolEntacapone may increase the central nervous system depressant (CNS depressant) activities of Ethanol.
HydrocodoneEntacapone may increase the central nervous system depressant (CNS depressant) activities of Hydrocodone.
HydroxyzineHydroxyzine may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
Iron DextranThe serum concentration of Entacapone can be decreased when it is combined with Iron Dextran.
LorazepamThe risk or severity of adverse effects can be increased when Lorazepam is combined with Entacapone.
LoxapineThe therapeutic efficacy of Loxapine can be decreased when used in combination with Entacapone.
Magnesium SulfateMagnesium Sulfate may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
MethotrimeprazineEntacapone may increase the central nervous system depressant (CNS depressant) activities of Methotrimeprazine.
MetyrosineEntacapone may increase the sedative activities of Metyrosine.
MinocyclineMinocycline may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
MirtazapineEntacapone may increase the central nervous system depressant (CNS depressant) activities of Mirtazapine.
NabiloneNabilone may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
OrphenadrineEntacapone may increase the central nervous system depressant (CNS depressant) activities of Orphenadrine.
ParaldehydeEntacapone may increase the central nervous system depressant (CNS depressant) activities of Paraldehyde.
ParoxetineThe risk or severity of adverse effects can be increased when Entacapone is combined with Paroxetine.
PerampanelPerampanel may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
PhenelzineThe risk or severity of adverse effects can be increased when Entacapone is combined with Phenelzine.
PipamperoneThe therapeutic efficacy of Pipamperone can be decreased when used in combination with Entacapone.
PramipexoleEntacapone may increase the sedative activities of Pramipexole.
RopiniroleEntacapone may increase the sedative activities of Ropinirole.
RotigotineEntacapone may increase the sedative activities of Rotigotine.
RufinamideThe risk or severity of adverse effects can be increased when Rufinamide is combined with Entacapone.
Sodium oxybateSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
SuvorexantEntacapone may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.
TapentadolTapentadol may increase the central nervous system depressant (CNS depressant) activities of Entacapone.
ThalidomideEntacapone may increase the central nervous system depressant (CNS depressant) activities of Thalidomide.
TizanidineThe serum concentration of Tizanidine can be increased when it is combined with Entacapone.
TranylcypromineThe risk or severity of adverse effects can be increased when Entacapone is combined with Tranylcypromine.
ValsartanValsartan may increase the orthostatic hypotensive activities of Entacapone.
ZiprasidoneThe therapeutic efficacy of Entacapone can be decreased when used in combination with Ziprasidone.
ZolpidemEntacapone may increase the central nervous system depressant (CNS depressant) activities of Zolpidem.
Food Interactions
  • Take without regard to meals.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
O-methyltransferase activity
Specific Function:
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
Gene Name:
COMT
Uniprot ID:
P21964
Molecular Weight:
30036.77 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  2. Najib J: Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease. Clin Ther. 2001 Jun;23(6):802-32; discussion 771. [PubMed:11440283 ]
  3. Chong BS, Mersfelder TL: Entacapone. Ann Pharmacother. 2000 Sep;34(9):1056-65. [PubMed:10981253 ]
  4. Holm KJ, Spencer CM: Entacapone. A review of its use in Parkinson's disease. Drugs. 1999 Jul;58(1):159-77. [PubMed:10439935 ]
  5. Poewe WH, Deuschl G, Gordin A, Kultalahti ER, Leinonen M: Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand. 2002 Apr;105(4):245-55. [PubMed:11939936 ]
  6. Brooks DJ, Sagar H: Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson's disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry. 2003 Aug;74(8):1071-9. [PubMed:12876237 ]
  7. Forsberg M, Lehtonen M, Heikkinen M, Savolainen J, Jarvinen T, Mannisto PT: Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat. J Pharmacol Exp Ther. 2003 Feb;304(2):498-506. [PubMed:12538800 ]
  8. Tai CH, Wu RM: Catechol-O-methyltransferase and Parkinson's disease. Acta Med Okayama. 2002 Feb;56(1):1-6. [PubMed:11873938 ]
  9. Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. [PubMed:10882160 ]
  10. Ruottinen HM, Rinne UK: COMT inhibition in the treatment of Parkinson's disease. J Neurol. 1998 Nov;245(11 Suppl 3):P25-34. [PubMed:9808337 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
O-methyltransferase activity
Specific Function:
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
Gene Name:
COMT
Uniprot ID:
P21964
Molecular Weight:
30036.77 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Retinoic acid binding
Specific Function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1.
Gene Name:
UGT1A9
Uniprot ID:
O60656
Molecular Weight:
59940.495 Da
References
  1. Lautala P, Ethell BT, Taskinen J, Burchell B: The specificity of glucuronidation of entacapone and tolcapone by recombinant human UDP-glucuronosyltransferases. Drug Metab Dispos. 2000 Nov;28(11):1385-9. [PubMed:11038168 ]
  2. Kurkela M, Garcia-Horsman JA, Luukkanen L, Morsky S, Taskinen J, Baumann M, Kostiainen R, Hirvonen J, Finel M: Expression and characterization of recombinant human UDP-glucuronosyltransferases (UGTs). UGT1A9 is more resistant to detergent inhibition than other UGTs and was purified as an active dimeric enzyme. J Biol Chem. 2003 Feb 7;278(6):3536-44. Epub 2002 Nov 14. [PubMed:12435745 ]
  3. Luukkanen L, Taskinen J, Kurkela M, Kostiainen R, Hirvonen J, Finel M: Kinetic characterization of the 1A subfamily of recombinant human UDP-glucuronosyltransferases. Drug Metab Dispos. 2005 Jul;33(7):1017-26. Epub 2005 Mar 31. [PubMed:15802387 ]
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Drug created on June 13, 2005 07:24 / Updated on May 31, 2016 02:12