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| Targets |
Entacapone acid targets and inhibits catechol-O-methyltransferase (COMT). In vitro studies show that entacapone has an IC₅₀ of 10 nM against rat duodenum COMT and 160 nM against rat liver soluble COMT. It exhibits an IC₅₀ of 20.1 nM against rat liver total COMT with a Ki of 10.7 nM. The IC₅₀ values against soluble COMT (S-COMT) and membrane-bound COMT (MB-COMT) are 14.3 nM and 73.3 nM, respectively. Entacapone demonstrates reversible, tight-binding type inhibition with a Ki of 14 nM against soluble rat liver COMT.
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| ln Vitro |
Entacapone acid is a specific, potent, and reversible inhibitor of COMT. In vitro enzyme assays show that entacapone inhibits rat duodenum COMT with an IC₅₀ of 10 nM and rat liver soluble COMT with an IC₅₀ of 160 nM. It exhibits an IC₅₀ of 20.1 nM against rat liver total COMT with a Ki of 10.7 nM. Entacapone has no effect on other catecholamine-metabolizing enzymes, demonstrating high selectivity. Comparative studies indicate that entacapone has a Ki of 10.7 nM against rat liver COMT, comparable in potency to tolcapone (Ki of 10.0 nM).
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| ln Vivo |
Peripheral COMT Inhibition: In rat models, oral administration of entacapone (3-30 mg/kg) together with levodopa + carbidopa dose-dependently reduces serum concentration of the O-methylated metabolite 3-O-methyldopa while increasing levodopa concentration and significantly elevating striatal dopamine concentration.
COMT Inhibition Dose-Response: One hour after oral dosing, the entacapone doses required to produce 50% inhibition of rat duodenal, erythrocyte, liver, and striatal COMT activity are 1.1, 5.4, 6.7, and 24.2 mg/kg, respectively.
CNS Penetration: Entacapone exhibits poor penetration into the brain. Even at the highest dose of 30 mg/kg, the formation of homovanillic acid, the O-methyl metabolite of dopamine in the striatum, is not reduced, confirming its predominantly peripheral action.
Pharmacodynamic Profile: Following a single oral dose (10 mg/kg), entacapone produces an equal maximal degree of COMT inhibition in peripheral tissues compared to tolcapone but is less effective at inhibiting striatal COMT. After 7 days of twice-daily treatment, COMT activity recovers to 67-101% of control within 8 hours after the last entacapone dose, indicating a shorter duration of action.
Levodopa Dose-Sparing Effect: When entacapone is added to levodopa + carbidopa treatment, the levodopa dose required to produce the same striatal dopamine concentration can be reduced from 50 mg/kg to 15 mg/kg.
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| Enzyme Assay |
In rat liver COMT inhibition assays, entacapone is dissolved in an appropriate solvent and incubated with purified rat liver COMT enzyme and substrate. Methylated product formation is measured to calculate IC₅₀ and Ki values. Alternatively, erythrocyte COMT activity assays are performed: blood samples are collected, erythrocytes are isolated, and COMT methylation activity toward substrates is measured to calculate the percentage inhibition relative to baseline.
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| Animal Protocol |
Oral Administration Study: Male rats receive oral entacapone (3-30 mg/kg) together with levodopa (50 mg/kg) + carbidopa (50 mg/kg). Blood samples are collected at multiple time points post-administration, and serum concentrations of levodopa and 3-O-methyldopa are measured by HPLC. Striatal concentrations of dopamine, 3-methoxytyramine, and homovanillic acid are also measured.
Intravenous and Oral Administration Comparison: Rats receive intravenous entacapone (3 mg/kg) or oral entacapone (10 mg/kg). Plasma concentrations and COMT inhibition activity are measured. The elimination half-life of entacapone after intravenous administration is 0.8 hours.
Bioavailability Study: Rats are orally administered various entacapone formulations (suspension, solution, HP-β-CD solution, etc.). Plasma concentrations and erythrocyte COMT inhibition are measured. The oral bioavailability of entacapone suspension is 8.9%, while the solution formulation exhibits 34.8% bioavailability.
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| ADME/Pharmacokinetics |
Entacapone acid (free acid) has a molecular weight of 250.16, while the active pharmaceutical ingredient entacapone has a molecular weight of 305.29. Entacapone is rapidly absorbed following oral administration, with a time to maximum concentration of approximately 1 hour. Absolute oral bioavailability is approximately 35%, influenced by first-pass metabolism. Plasma protein binding is high at 98%, resulting in limited tissue distribution. The elimination half-life after intravenous administration is approximately 0.4-0.7 hours (β phase) and 2.4 hours (γ phase). Entacapone is almost completely metabolized before urinary excretion, with only 0.1-0.2% of the dose excreted unchanged. It is soluble in DMSO but insoluble in water. Storage conditions: Store at room temperature protected from light.
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| Toxicity/Toxicokinetics |
Safety Profile: Entacapone is generally well tolerated and is not associated with hepatotoxicity, making it superior to tolcapone, which carries a risk of liver damage. Comparative toxicity studies indicate that lipophilicity is a key determinant of nitrocatechol toxicity, and entacapone exhibits lower reactivity and cytotoxicity due to its cyano moiety in a double bond structure.
Adverse Effects: In clinical use, adverse effects of entacapone are primarily related to increased levodopa exposure, including dyskinesias, nausea, diarrhea, and orange discoloration of urine. Evidence from multiple studies confirms that entacapone does not cause hepatotoxicity.
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| References | |
| Additional Infomation |
Entacapone acid (CAS: 160391-70-8) is a different substance from entacapone (free base/active pharmaceutical ingredient). The former is designated as Impurity F of entacapone in the European Pharmacopoeia (EP) and has a molecular weight of 250.16; the latter is the active pharmaceutical ingredient with a molecular weight of 305.29, the difference being one molecule of water. Entacapone acid is primarily used as a reference standard for pharmaceutical quality control, while entacapone is a COMT inhibitor clinically used for the treatment of Parkinson's disease. Due to the differences in their molecular formulas and molecular weights, they should not be used interchangeably.
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| Molecular Formula |
C10H6N2O6
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| Molecular Weight |
250.17
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| Exact Mass |
250.022
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| Elemental Analysis |
C, 48.01; H, 2.42; N, 11.20; O, 38.37
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| CAS # |
160391-70-8
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| Related CAS # |
130929-57-6; 1047659-02-8
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| PubChem CID |
23189849
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| Appearance |
Light brown to brown solid at room temperature
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| Density |
1.7±0.1 g/cm3
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| Boiling Point |
478.9±45.0 °C at 760 mmHg
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| Flash Point |
243.4±28.7 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.750
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| LogP |
2.19
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
18
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| Complexity |
431
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N#C/C(=C\C1C=C(O)C(O)=C([N+]([O-])=O)C=1)/C(=O)O
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| InChi Key |
XDDDOLQEZBJWFZ-LZCJLJQNSA-N
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| InChi Code |
InChI=1S/C10H6N2O6/c11-4-6(10(15)16)1-5-2-7(12(17)18)9(14)8(13)3-5/h1-3,13-14H,(H,15,16)/b6-1+
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| Chemical Name |
(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)prop-2-enoic acid
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| Synonyms |
Entacapone acid AG-1290; Entacapone acid; 160391-70-8; Tyrphostin AG 1290; (2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)prop-2-enoic acid; Entacapone impurity F [EP]; AG 1290
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.9973 mL | 19.9864 mL | 39.9728 mL | |
| 5 mM | 0.7995 mL | 3.9973 mL | 7.9946 mL | |
| 10 mM | 0.3997 mL | 1.9986 mL | 3.9973 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02058966 | COMPLETEDWITH RESULTS | Drug: Entacapone Drug: Methamphetamine Drug: Placebo |
Methamphetamine Dependence | Oregon Health and Science University | 2014-06 | Early Phase 1 |
| NCT00547911 | TERMINATEDWITH RESULTS | Drug: Droxidopa Drug: Carbidopa Drug: Entacapone |
Autonomic Nervous System Diseases Multiple System Atrophy Parkinson Disease |
National Institute of Neurological Disorders and Stroke (NINDS) | 2007-10 | Phase 1 Phase 2 |
| NCT00415740 | COMPLETED | Drug: ELC200 (carbidopa+levodopa+entacapone) | Healthy | Novartis | 2006-05 | Phase 1 |
| NCT00415922 | COMPLETED | Drug: ELC200 (carbidopa+levodopa+entacapone) | Healthy | Novartis | 2006-07 | Phase 1 |
| NCT00415831 | COMPLETED | Drug: ELC200 (carbidopa+levodopa+entacapone) | Healthy | Novartis | 2006-06 | Phase 1 |
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