5-(4-methylbenzoyl)-3-nitrobenzene-1,2-diol

• ChemBase ID: 208
• Molecular Formular: C14H11NO5
• Molecular Mass: 273.24084
• Monoisotopic Mass: 273.06372246
• SMILES: O=C(c1cc([N+](=O)[O-])c(O)c(O)c1)c1ccc(cc1)C
• Canonical SMILES: Cc1ccc(cc1)C(=O)c1cc(O)c(c(c1)[N+](=O)[O-])O
• InChI: InChI=1S/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3
• InChIKey: MIQPIUSUKVNLNT-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 5-(4-methylbenzoyl)-3-nitrobenzene-1,2-diol
• IUPAC Traditional name: tolcapone; tolcapone (product); 5-(4-methylbenzoyl)-3-nitrobenzene-1,2-diol
• Brand Name: Tasmar
• Synonyms: (3,4-Dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone; Ro-40-7592; Tasmar; (3,4-dihydroxy-5-nitrophenyl)(p-tolyl)methanone; 3,4-Dihydroxy-4′-methyl-5-nitrobenzophenone; Ro 40-7592; Tolcapone; Tolcapone

Database IDs

• CAS Number: 134308-13-7
• MDL Number: MFCD00866569
• PubChem SID: 160963671; 46504932
• PubChem CID: 4659569

CALCULATED PROPERTIES

JChem

• Acid pKa: 5.437702
• H Acceptors: 5
• H Donor: 2
• LogD (pH = 5.5): 2.9509084
• LogD (pH = 7.4): 1.6083276
• Log P: 3.2788737
• Molar Refractivity: 71.957 cm^3
• Polarizability: 26.861366 Å^3
• Polar Surface Area: 100.67 Å^2
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.63
• LOG S: -3.68
• Solubility (Water): 5.69e-02 g/l

PROPERTIES

Physical Property

• Solubility: Chloroform; DMSO: ≥15 mg/mL; Methanol
• Apperance: yellow powder; Yellow Solid
• Melting Point: 138-140°C
• Hydrophobicity(logP): 4

Safety Information

• Storage Condition: -20°C Freezer; desiccated
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: Transferase

Product Information

• Purity: ≥98% (HPLC); 98%
• Salt Data: Free Base
• Empirical Formula (Hill Notation): C14H11NO5

DETAILS

DrugBank - DB00323

• Drug Groups: approved; withdrawn
• Description: Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase (COMT). It is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication. It is a yellow, odorless, non-hygroscopic, crystalline compound. Tolcapone is associated with a risk of hepatotoxicity. [Wikipedia]
• Indication: Used as an adjunct to levodopa/carbidopa therapy for the symptomatic treatment of Parkinson's Disease. This drug is generally reserved for patients with parkinsonian syndrome receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to or are not candidates for other adjunctive therapies.
• Pharmacology: Tolcapone is a potent, selective, and reversible inhibitor of catechol-O-methyltransferase (COMT). In humans, COMT is distributed throughout various organs. 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, 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 it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa.
• Toxicity: LD₅₀ = 1600 mg/kg (Orally in rats)
• Affected Organisms: Humans and other mammals
• Biotransformation: The main metabolic pathway of tolcapone is glucuronidation
• Absorption: Rapidly absorbed (absolute bioavailability is about 65%)
• Half Life: 2-3.5 hours
• Protein Binding: > 99.9% (to serum albumin)
• Elimination: Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile.
• Distribution: * 9 L
• Clearance: * 7 L/h
• References: Guay DR: Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease. Pharmacotherapy. 1999 Jan;19(1):6-20. [Pubmed] ; Keating GM, Lyseng-Williamson KA: Tolcapone: a review of its use in the management of Parkinson's disease. CNS Drugs. 2005;19(2):165-84. [Pubmed] ; Truong DD: Tolcapone: review of its pharmacology and use as adjunctive therapy in patients with Parkinson's disease. Clin Interv Aging. 2009;4:109-13. Epub 2009 May 14. [Pubmed] ; 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] ; 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: Wikipedia; RxList; PDRhealth; Drugs.com

Sigma Aldrich - SML0150

Biochem/physiol Actions
Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor. It inhibits both central and peripheral COMT. Tolcapone crosses the blood-brain barrier, and has been used for L-DOPA adjunct therapy in the treatment of Parkinson′s Disease.

Toronto Research Chemicals - T535250

Orally active inhibitor of central and peripheral catechol-O-methyltransferase (COMT). Antiparkinsonian.

REFERENCES

• Guay DR: Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease. Pharmacotherapy. 1999 Jan;19(1):6-20. Pubmed
• Keating GM, Lyseng-Williamson KA: Tolcapone: a review of its use in the management of Parkinson's disease. CNS Drugs. 2005;19(2):165-84. Pubmed
• Truong DD: Tolcapone: review of its pharmacology and use as adjunctive therapy in patients with Parkinson's disease. Clin Interv Aging. 2009;4:109-13. Epub 2009 May 14. Pubmed
• 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
• Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. Pubmed
• Dingemanse, J., et al.: Clin. Pharmacol. Ther., 57, 508 (1995)
• Keating, K.A., Drugs, 19, 165 (1995)