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Identification
Name Entacapone
Accession Number DB00494 (APRD00416)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Entacapona [INN-Spanish]
  • Entacapone [Usan:Inn]
  • Entacaponum [INN-Latin]
Synonyms
Entacapona [INN-Spanish]
Entacapone [Usan:Inn]
Entacaponum [INN-Latin]
Salts Not Available
Brand names
Name Company
Comtan
Comtess
Brand mixtures Not Available
Categories
  • Central Nervous System Agents
  • Antiparkinson Agents
  • Antidyskinetics
  • Enzyme Inhibitors
CAS number 130929-57-6
Weight Average: 305.286
Monoisotopic: 305.101170605
Chemical Formula C14H15N3O5
InChI Key InChIKey=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+
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Nitrobenzenes
  • Phenylpropenes
  • Nitrophenols and Derivatives
  • Aminophenols and Derivatives
  • Cinnamaldehydes
Substructures
  • Hydroxy Compounds
  • Phenols and Derivatives
  • Alkanes and Alkenes
  • Nitrobenzenes
  • Oxoazaniums
  • Amino Ketones
  • Phenylpropenes
  • Nitriles and Derivatives
  • Nitrophenols and Derivatives
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Aminophenols and Derivatives
  • Nitro compounds
  • Cyanides
  • Catechols
  • Aromatic compounds
  • Cinnamaldehydes
  • Carboxamides and Derivatives
  • Styrene Derivatives
  • Phenyl Esters
  • Anilines
Pharmacology
Indication Used 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".
Pharmacodynamics Entacapone 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 action The 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.
Absorption Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.
Volume of distribution
  • 20 L
Protein binding 98% (bind to serum albumin)
Metabolism Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer.
Route of elimination Entacapone 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 life 0.4-0.7 hour
Clearance
  • 850 mL/min
Toxicity Side 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Orion corp
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Comtan 200 mg tablet 2.96 USD tablet
Patents
Country Patent Number Approved Expires (estimated)
United States 6599530 1998-09-14 2018-09-14
United States 5135950 1993-10-31 2010-10-31
Canada 2342634 2008-01-29 2019-09-13
Canada 1334967 1995-03-28 2012-03-28
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP 2.8 PhysProp
Predicted Properties
Property Value Source
water solubility 7.97e-02 g/l ALOGPS
logP 2.5 ALOGPS
logP 1.63 ChemAxon Molconvert
logS -3.6 ALOGPS
pKa 10.72 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 130.38 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 80.51 ChemAxon Molconvert
polarizability 29.48 ChemAxon Molconvert
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00781 Link_out
KEGG Compound C07943 Link_out
PubChem Compound 5281081 Link_out
PubChem Substance 46508734 Link_out
ChemSpider 4444537 Link_out
ChEBI 4798 Link_out
ChEMBL 4798 Link_out
Therapeutic Targets Database DAP000608 Link_out
PharmGKB PA449464 Link_out
Drug Product Database 2243763 Link_out
RxList http://www.rxlist.com/cgi/generic3/entac.htm Link_out
Drugs.com http://www.drugs.com/cdi/entacapone.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Entacapone Link_out
ATC Codes
  • N04BX02
AHFS Codes
  • 28:92.00
PDB Entries Not Available
FDA label show (52.6 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Apomorphine Entacapone increases the effect and toxicity of the sympathomimetic, apomorphine.
Bitolterol Entacapone may increase the effect and toxicity of bitolterol.
Dobutamine Entacapone increases the effect and toxicity of the sympathomimetic, dobutamine.
Dopamine Entacapone increases the effect and toxicity of the sympathomimetic, dopamine.
Epinephrine Entacapone may increase the effect and toxicity of the sympathomimetic, epinephrine.
Isocarboxazid Possible hypertensive crisis with this combination
Isoetharine Entacapone increases the effect and toxicity of the sympathomimetic, isoetharine.
Isoproterenol Entacapone increases the effect and toxicity of the sympathomimetic, isoproterenol.
Methyldopa Entacapone may increase the effect and toxicity of the sympathomimetic, methyldopa.
Norepinephrine Entacapone increases the effect and toxicity of the sympathomimetic, norepinephrine.
Phenelzine Possible hypertensive crisis with this combination
Tranylcypromine Additive inhibition of endogenous catecholamine metabolism may increase the therapeutic/adverse effects of both agents. Concomitant therapy should be avoided.
Triprolidine The 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

Pharmacological action: yes
Actions: inhibitor

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

Organism class: human
UniProt ID: P21964 Link_out
Gene: COMT Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

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

UniProt ID: P21964 Link_out
Gene: COMT Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols

UniProt ID: O60656 Link_out
Gene: UGT1A9 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:42