Tolcapone

Summary

Tolcapone (CHEMBL1324) is an approved small-molecule EC 2.1.1.6 (catechol O-methyltransferase) inhibitor (ATC N04BX01) targeting COMT; indicated across 14 conditions including liver failure and parkinson disease.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: N04BX01
• Targets: 1 (COMT)
• Indications: 14 conditions
• Clinical trials: 26
• Chemistry: 273.24 Da · C14H11NO5

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1324
Name	Tolcapone
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	4659569
ChEBI	CHEBI:63630
ATC	N04BX01
Molecular formula	C14H11NO5
Molecular weight	273.24
InChIKey	MIQPIUSUKVNLNT-UHFFFAOYSA-N

SMILES: CC1=CC=C(C=C1)C(=O)C2=CC(=C(C(=C2)O)O)[N+](=O)[O-]

IUPAC name: (3,4-dihydroxy-5-nitrophenyl)-(4-methylphenyl)methanone

ChEBI definition: Benzophenone substituted on one of the phenyl rings at C-3 and C-4 by hydroxy groups and at C-5 by a nitro group, and on the other phenyl ring by a methyl group at C-4. It is an inhibitor of catechol O-methyltransferase.

Pharmacological roles (ChEBI): EC 2.1.1.6 (catechol O-methyltransferase) inhibitor, antiparkinson drug.

Also known as: RO-407592, Tasmar, Tolcapona, Tolcapone, Talcapone, tolcapone, TOLCAPONE, SID50126317, SID144206516, SID170465081, SID144212731, TolcaponeÊ

Patent coverage: 3,343 distinct patent families (13,819 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 13,737 (99%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
COMT	Catechol-O-methyltransferase	Inhibition	9.54	2.1%	P21964

Broader ChEMBL bioactivity targets: 27 (assay-derived). Sample: G-protein coupled receptor 35, ATP-binding cassette sub-family C member 4, Retinoic acid receptor beta, Catechol O-methyltransferase, Glucocorticoid receptor, Bile salt export pump, Progesterone receptor, 5-hydroxytryptamine receptor 1A, Sodium-dependent noradrenaline transporter, Adenosine receptor A1.

Bioactivity

ChEMBL activities: 38 potent at pChembl ≥ 5 of 57 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P22734	9.04	IC50	0.91	nM	CHEMBL_ACT_19443156
P22734	9.04	IC50	0.91	nM	CHEMBL_ACT_19443219
P22734	8.66	IC50	2.2	nM	CHEMBL_ACT_16489805
P22734	8.66	IC50	2.2	nM	CHEMBL_ACT_533901
P22734	8.52	IC50	3	nM	CHEMBL_ACT_25582521
P22734	8.4	IC50	4	nM	CHEMBL_ACT_29060434
P22734	7.77	IC50	17	nM	CHEMBL_ACT_25582510
P22734	7.7	IC50	20	nM	CHEMBL_ACT_29060427
TTR	7.69	Kd	20.6	nM	CHEMBL_ACT_18557076
P22734	7.51	IC50	30.59	nM	CHEMBL_ACT_19443172
TTR	7.47	Kd	34	nM	CHEMBL_ACT_24670675
TTR	7.47	Kd	34	nM	CHEMBL_ACT_24670680
TTR	7.32	Kd	48	nM	CHEMBL_ACT_25518122
TTR	7.3	Kd	50	nM	CHEMBL_ACT_25518138
P22734	7.28	IC50	53	nM	CHEMBL_ACT_25582492
TTR	7.25	Kd	56	nM	CHEMBL_ACT_18557150
P22734	7.17	IC50	67	nM	CHEMBL_ACT_29060420
TTR	7.02	Kd	95	nM	CHEMBL_ACT_23263058
COMT	6.9	IC50	127	nM	CHEMBL_ACT_16622761
TTR	6.36	Kd	440	nM	CHEMBL_ACT_25518130
P29990	6.19	IC50	640	nM	CHEMBL_ACT_19235338
P29990	6.19	IC50	640	nM	CHEMBL_ACT_24666549
P29990	6.19	IC50	640	nM	CHEMBL_ACT_24666551
P29990	6.19	IC50	640	nM	CHEMBL_ACT_24666556
P29990	6.19	IC50	640	nM	CHEMBL_ACT_24666607
P06935	6.16	IC50	700	nM	CHEMBL_ACT_24971864
P15207	6.12	AC50	762.9	nM	CHEMBL_ACT_25187677
P22734	6.03	IC50	930	nM	CHEMBL_ACT_1653722
TTR	6.01	Kd	980	nM	CHEMBL_ACT_23262932
SLC6A3	5.96	AC50	1100	nM	CHEMBL_ACT_25124388

Target pathways

Aggregated over 1 target gene(s): COMT.

Top Reactome pathways

4 total, by targets touching each:

Pathway	Targets	Genes
Methylation	1	COMT
Enzymatic degradation of dopamine by COMT	1	COMT
Enzymatic degradation of Dopamine by monoamine oxidase	1	COMT
Potential therapeutics for SARS	1	COMT

Dominant GO biological processes

GO term	Targets
behavioral fear response	1
response to hypoxia	1
synaptic transmission, dopaminergic	1
startle response	1
response to amphetamine	1
renin secretion into blood stream	1
glycogen metabolic process	1
prostaglandin metabolic process	1
response to oxidative stress	1
memory	1
visual learning	1
response to xenobiotic stimulus	1
response to wounding	1
response to toxic substance	1
gene expression	1

Indications & clinical

Indications

14 indications (2 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
liver failure	4	MONDO:0100192	HP:0001399
Parkinson disease	4	MONDO:0005180	MONDO:0005180
nicotine dependence	2	MONDO:0008575	EFO:0003768
pathological gambling	2	MONDO:0011662	EFO:0004699
Pick disease	2	MONDO:0008243	EFO:0003096
obsessive-compulsive disorder	2	MONDO:0008114	EFO:0004242
alcohol abuse	2	MONDO:0002046	MONDO:0002046
brain injury	2	MONDO:0043510	MONDO:0043510
neuroblastoma	1	MONDO:0005072	EFO:0000621
cocaine dependence	1	MONDO:0005186	EFO:0002610
familial amyloid neuropathy	0	MONDO:0007100	EFO:0004129

3 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 26.

Phase distribution

Phase	Trials
PHASE2	12
PHASE1	5
EARLY_PHASE1	3
Not specified	3
PHASE4	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00906828	PHASE4	COMPLETED	Pharmacokinetics of Levodopa/Carbidopa Infusion With and Without Oral Catechol-O-methyl Transferase (COMT) Inhibitors
NCT02929485	PHASE4	WITHDRAWN	Dopaminergic Modulation of Frontostriatal Function With a Dopamine Agonist and COMT Inhibitor
NCT03348930	PHASE2/PHASE3	COMPLETED	Tolcapone in Obsessive Compulsive Disorder
NCT05624528	PHASE2	ACTIVE_NOT_RECRUITING	A Clinical Trial of Tolcapone in Obsessive Compulsive Disorder
NCT00044083	PHASE2	TERMINATED	Clinical Trial of Tolcapone for Cognition in Schizophrenia
NCT00604591	PHASE2	COMPLETED	Effects of Tolcapone on Frontotemporal Dementia
NCT00927563	PHASE2	COMPLETED	Tolcapone Treatment of Pathological Gambling
NCT01001520	PHASE2	COMPLETED	Neural Substrates in Nicotine Withdrawal
NCT01202955	PHASE2	COMPLETED	Pilot Study of Tolcapone in Smokers
NCT02652598	PHASE2	UNKNOWN	Evaluate the Effects of Tolcapone on Cognitive and Behavioral Dysfunction in Patients With BI and NCD
NCT02740582	PHASE2	COMPLETED	Effects of Tolcapone on Decision Making and Alcohol Intake in Alcohol Users
NCT02949934	PHASE2	COMPLETED	Effects of Cortical Dopamine Regulation on Drinking, Craving, and Cognitive Control
NCT03273062	PHASE2	UNKNOWN	A Trial Evaluating Effects of COMT Inhibition in Patients With Acquired Brain Injury
NCT03904498	PHASE2	COMPLETED	COMT Inhibition Among Individuals With Comorbid AUD/ADHD
NCT06387771	PHASE2	UNKNOWN	Evaluation of Tolcapone as a Cognitive Enhancer in Schizophrenia
NCT00033059	PHASE1	UNKNOWN	Assessment of Potential Interactions Between Cocaine and Tolcapone - 1
NCT02080715	PHASE1	COMPLETED	Role of the Catechol-O-methyltransferase (COMT) in the Physiological Regulation of Vigilance
NCT02630043	PHASE1	TERMINATED	Trial of Tolcapone With Oxaliplatin for Neuroblastoma
NCT03633591	PHASE1	COMPLETED	A Study Assessing the Safety and Pharmacokinetic Profile of Modified Release Formulations of Tolcapone
NCT05065671	PHASE1	COMPLETED	Microbiome Derived Metabolism and Pharmacokinetics
NCT02260570	EARLY_PHASE1	COMPLETED	Remediation of Impaired Self-Regulation in Patients With Mild TBI
NCT03591757	EARLY_PHASE1	COMPLETED	Short-term Effects of TOLCAPONE on Transthyretin Stability in Subjects With Leptomeningeal TTR Amyloidosis (ATTR)
NCT04205994	EARLY_PHASE1	COMPLETED	Dopaminergic Mechanisms Underlying Human Social Behavior
NCT01158950	Not specified	COMPLETED	A Study of Neural Circuit Responses to Catechol-O-methyl Transferase (COMT) Inhibitors
NCT02448654	Not specified	COMPLETED	Treatment for Nicotine Addiction in Women
NCT02772978	Not specified	COMPLETED	Dopamine Responsivity in Gamblers

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 0 clinical and 5 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

15 molecules share ≥1 primary target. Top 15 by shared-target count:

Molecule	Source	Status	Shared targets
ENTACAPONE	ChEMBL	Phase 4 (approved)	COMT
OPICAPONE	ChEMBL	Phase 4 (approved)	COMT
Afatinib	PubChem	Approved	COMT
alfaxalone	PubChem	Approved	COMT
Apixaban	PubChem	Approved	COMT
Binimetinib	PubChem	Approved	COMT
Diacetyl benzoyl lathyrol	PubChem	Approved	COMT
Edoxaban	PubChem	Approved	COMT
Fulvestrant	PubChem	Approved	COMT
Imipenem	PubChem	Approved	COMT
Linagliptin	PubChem	Approved	COMT
Pazopanib	PubChem	Approved	COMT
Pimavanserin	PubChem	Approved	COMT
Pyrazinamide	PubChem	Approved	COMT
Selumetinib	PubChem	Approved	COMT