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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
SynonymLanguageCode
(e)-alpha-Cyano-N,N-diethyl-3,4-dihydroxy-5-nitrocinnamamideNot AvailableNot Available
ComtanNot AvailableNot Available
ComtessNot AvailableNot Available
EntacaponaSpanishINN
EntacaponeFrenchINN, USAN, DCF
EntacaponumLatinINN
N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamideNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AnxoponeRoot
ComtadeNovartis
ComtanOrion
ComtessOrion
Brand mixtures
Brand NameIngredients
StalevEntacapone and Levodopa, + Carbidopa
StalevoEntacapone and Levodopa, + Carbidopa
Categories
CAS number130929-57-6
WeightAverage: 305.286
Monoisotopic: 305.101170605
Chemical FormulaC14H15N3O5
InChI KeyJRURYQJSLYLRLN-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassCinnamic Acids and Derivatives
SubclassCinnamic Acid Amides
Direct parentCinnamic Acid Amides
Alternative parentsHydroxycinnamic Acids and Derivatives; Nitrophenols and Derivatives; Nitrobenzenes; Phenylpropenes; Aminophenols; Catechols; Tertiary Carboxylic Acid Amides; Enones; Tertiary Amines; Nitro Compounds; Polyols; Nitronic Acids; Enols; Polyamines; Enolates; Nitriles; Carboxylic Acids; Organic Oxoazanium Compounds
Substituentsnitrophenol derivative; nitrobenzene; phenylpropene; aminophenol; 1,2-diphenol; phenol derivative; benzene; enone; tertiary carboxylic acid amide; carboxamide group; polyol; nitro compound; tertiary amine; nitronic acid; enolate; carboxylic acid derivative; carbonitrile; nitrile; carboxylic acid; enol; organic oxoazanium; polyamine; organonitrogen compound; amine
Classification descriptionThis compound belongs to the cinnamic acid amides. These are amides of cinnamic acids.
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.
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
Property Value Probability
Human Intestinal Absorption + 0.9185
Blood Brain Barrier - 0.9104
Caco-2 permeable - 0.5817
P-glycoprotein substrate Substrate 0.64
P-glycoprotein inhibitor I Non-inhibitor 0.7342
P-glycoprotein inhibitor II Non-inhibitor 0.8442
Renal organic cation transporter Non-inhibitor 0.9311
CYP450 2C9 substrate Non-substrate 0.8406
CYP450 2D6 substrate Non-substrate 0.8932
CYP450 3A4 substrate Non-substrate 0.5057
CYP450 1A2 substrate Non-inhibitor 0.7003
CYP450 2C9 substrate Non-inhibitor 0.581
CYP450 2D6 substrate Non-inhibitor 0.8548
CYP450 2C19 substrate Non-inhibitor 0.6098
CYP450 3A4 substrate Non-inhibitor 0.5133
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7901
Ames test AMES toxic 0.5803
Carcinogenicity Non-carcinogens 0.561
Biodegradation Not ready biodegradable 0.9457
Rat acute toxicity 2.6750 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8608
hERG inhibition (predictor II) Non-inhibitor 0.8332
Pharmacoeconomics
Manufacturers
  • Orion corp
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Comtan 200 mg tablet2.96USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States65995301998-09-142018-09-14
United States51359501993-10-312010-10-31
Canada23426342008-01-292019-09-13
Canada13349671995-03-282012-03-28
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP2.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0797ALOGPS
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
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 Reference
  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
  2. Chong BS, Mersfelder TL: Entacapone. Ann Pharmacother. 2000 Sep;34(9):1056-65. Pubmed
  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
  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
  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
  6. Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs. 2000 Jun;59(6):1233-50. Pubmed
External Links
ResourceLink
KEGG DrugD00781
KEGG CompoundC07943
PubChem Compound5281081
PubChem Substance46508734
ChemSpider4444537
ChEBI4798
ChEMBLCHEMBL953
Therapeutic Targets DatabaseDAP000608
PharmGKBPA164748726
Drug Product Database2243763
RxListhttp://www.rxlist.com/cgi/generic3/entac.htm
Drugs.comhttp://www.drugs.com/cdi/entacapone.html
WikipediaEntacapone
ATC CodesN04BX02
AHFS Codes
  • 28:92.00
PDB EntriesNot Available
FDA labelshow(52.6 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ApomorphineEntacapone increases the effect and toxicity of the sympathomimetic, apomorphine.
BitolterolEntacapone may increase the effect and toxicity of bitolterol.
DobutamineEntacapone increases the effect and toxicity of the sympathomimetic, dobutamine.
DopamineEntacapone increases the effect and toxicity of the sympathomimetic, dopamine.
EpinephrineEntacapone may increase the effect and toxicity of the sympathomimetic, epinephrine.
IsocarboxazidPossible hypertensive crisis with this combination
IsoetarineEntacapone increases the effect and toxicity of the sympathomimetic, isoetharine.
IsoprenalineEntacapone increases the effect and toxicity of the sympathomimetic, isoproterenol.
MethyldopaEntacapone may increase the effect and toxicity of the sympathomimetic, methyldopa.
NorepinephrineEntacapone increases the effect and toxicity of the sympathomimetic, norepinephrine.
PhenelzinePossible hypertensive crisis with this combination
TranylcypromineAdditive inhibition of endogenous catecholamine metabolism may increase the therapeutic/adverse effects of both agents. Concomitant therapy should be avoided.
TriprolidineThe CNS depressants, Triprolidine and Entacapone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food Interactions
  • Take without regard to meals.

Targets

1. Catechol O-methyltransferase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Catechol O-methyltransferase P21964 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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
  3. Chong BS, Mersfelder TL: Entacapone. Ann Pharmacother. 2000 Sep;34(9):1056-65. Pubmed
  4. Holm KJ, Spencer CM: Entacapone. A review of its use in Parkinson’s disease. Drugs. 1999 Jul;58(1):159-77. Pubmed
  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
  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
  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
  8. Tai CH, Wu RM: Catechol-O-methyltransferase and Parkinson’s disease. Acta Med Okayama. 2002 Feb;56(1):1-6. Pubmed
  9. Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs. 2000 Jun;59(6):1233-50. Pubmed
  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

Enzymes

1. Catechol O-methyltransferase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Catechol O-methyltransferase P21964 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. UDP-glucuronosyltransferase 1-9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-9 O60656 Details

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
  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
  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

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