Delving into the Latest Updates on Tolcapone with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone, 3,4-dihydroxy-5-nitro-4'-methylbenzophenone

+ [6]

Target

COMT

Mechanism

COMT inhibitors(Catechol-O-methyl transferase inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic DiseaseCongenital Disorders+ [1]

Active Indication

Parkinson DiseaseAmyloidosis, Hereditary, Transthyretin-Related

Inactive Indication-

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization

Viatris Healthcare (Pty) Ltd.

Hebei Aierhaitai Pharmacy Co. Ltd.

SOM Innovation Biotech SA

+ [2]

Inactive Organization-

Drug Highest PhaseApproved

First Approval Date

EU (27 Aug 1997),

Parkinson Disease

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC14H11NO5

InChIKeyMIQPIUSUKVNLNT-UHFFFAOYSA-N

CAS Registry134308-13-7

The investigators will perform single-dose pharmacokinetic (PK) studies in humans following administration of drugs with known microbiome derived metabolism (MDM) in parallel with preclinical studies. By directly comparing laboratory measurements to clinical results, the investigators will be able to confirm the relevance of MDM in vivo, create microbiome-dependent PK profiles of the MDM positive drugs, and establish methodology to capture the contribution of MDM to inter-individual variability in clinical drug PK profiles.

Start Date01 Feb 2022

Sponsor / Collaborator

Rutgers State University of New Jersey

100 Clinical Results associated with Tolcapone

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100 Translational Medicine associated with Tolcapone

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100 Patents (Medical) associated with Tolcapone

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551

Literatures (Medical) associated with Tolcapone

24 Oct 2024·Journal of Medicinal Chemistry

Discovery of a Potent, Selective, and Blood-Brain Barrier Permeable Non-nitrocatechol Inhibitor of Catechol-O-methyltransferase

Article

Author: Albuquerque, Bárbara ; Lima, Carla ; Cagide, Fernando ; Benfeito, Sofia ; Sequeira, Lisa ; Borges, Fernanda ; Serrão, Paula ; Chavarria, Daniel ; Soares-da-Silva, Patrício

A new library of non-nitrocatechol compounds (HetCAMs) was developed and their efficacy was compared to tolcapone, a standard COMT inhibitor for PD. Compound 9 emerged as the most potent inhibitor, showing selective inhibition of brain (IC₅₀ = 24 nM) and liver (IC₅₀ = 81 nM) MB-COMT over liver S-COMT (IC₅₀ = 620 nM) isoforms. Although compound 9 presented higher IC₅₀ values than tolcapone, it was more selective for brain MB-COMT than liver S-COMT. Unlike tolcapone, compound 9 is not a tight-binding inhibitor and is less cytotoxic to HepG2 and SK-N-SH cells. Additionally, compound 9 is predicted to cross the blood-brain barrier (BBB) by passive diffusion and chelate divalent metals like Fe(II) and Cu(II). The results demonstrate the potential of this rational drug design strategy for developing new CNS-active drug candidates, offering symptom relief via COMT inhibition that can provide a long-term, disease-modifying outcome (chelation of divalent metals) in PD.

13 Sep 2024·Science Advances

Modeling Lewy body disease with SNCA triplication iPSC-derived cortical organoids and identifying therapeutic drugs

Article

Author: Li, Fuyao ; Carr, Jonathan ; Caulfield, Thomas ; DeTure, Michael ; Dickson, Dennis W. ; Kanekiyo, Takahisa ; Santhakumar, Hannah ; Bu, Guojun ; Lu, Wenyan ; O’Leary, Justin ; Jin, Yunjung ; Ikezu, Tadafumi C. ; Selvaraj, Manikandan ; Martens, Yuka A. ; Zhao, Na ; Beasley, Alexandra I. ; McLean, Pamela J. ; Li, Yonghe ; Zhu, Yiyang ; Koga, Shunsuke ; Lolo, Kiara ; Ikezu, Tsuneya ; Li, Zonghua ; Ross, Owen A. ; You, Yang ; Wszolek, Zbigniew K. ; Davis, Mary D.

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)–derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration–approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

01 Sep 2024·Chemosphere

Formation of the emerging disinfection byproducts halocyclopentadienes from phenolic compounds after chlorination

Article

Author: Lin, Lihua ; Wang, Donghong ; Xu, Xiong ; Liu, Quanzhen ; Xie, Yongchang

Halocyclopentadienes (HCPDs) are an emerging class of alicyclic disinfection by-products (DBPs) with high toxicity in disinfected drinking water. However, their potential precursors remain unclear, which hinders the understanding of their formation and further development of control strategies. In this study, two HCPDs, 1,2,3,4-tetrachloro-1,3-cyclopentadiene (TCC) and 1,2,3,4,5,5-hexachloro-1,3-cyclopentadiene (HCC), were identified in chlorinated lignin and tannic acid samples for the first time. The chlorination of four lignin-like and two tannic-like phenolic model compounds confirmed that guaiacol and digallic acid can produce HCPDs. According to their structures, ortho-substituents of phenolic compounds were speculated to be crucial for HCPDs formation. The simulated disinfection of catechol, 2-ethoxyphenol (2-EOP), 2-propoxyphenol (2-POP) and 3,4-dihydroxy-5-methoxybenzoic acid (DH-5-MBA) with different ortho-substituents demonstrated that three of these compounds can generate HCPDs, except catechol, which further indicates that ortho-substituents, such as the methoxy, ethoxy and propoxy groups, contribute to HCPDs generation. Guaiacol was the simplest compound for generating HCPDs, and possible formation pathways during chlorination were proposed. Seven hydroxy-chlorocyclopentadienes were tentatively identified and are likely important intermediates of HCPDs formation. Additionally, TCC and HCC were confirmed in tap water and chlorinated SRNOM samples with total concentrations up to 11.07 ng/L and 65.66 ng/L, respectively, further demonstrating the wide existence of HCPDs and their precursors. This study reports the clear precursors of HCPDs and provides a theoretical foundation for controlling HCPDs formation in disinfected drinking water.

100 Deals associated with Tolcapone

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External Link

KEGG	Wiki	ATC	Drug Bank
D00786	Tolcapone	N04BX01	DB00323

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Parkinson Disease	LI	Viatris Healthcare (Pty) Ltd.	27 Aug 1997
Parkinson Disease	NO	Viatris Healthcare (Pty) Ltd.	27 Aug 1997
Parkinson Disease	EU	Viatris Healthcare (Pty) Ltd.	27 Aug 1997
Parkinson Disease	IS	Viatris Healthcare (Pty) Ltd.	27 Aug 1997

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Amyloidosis, Hereditary, Transthyretin-Related	Phase 2	ES	Corino Therapeutics, Inc.	30 Jan 2022
Amyloid Neuropathies, Familial	Phase 1	ES	SOM Innovation Biotech SA	01 Jul 2014

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02949934 (CTgov)	Phase 2	Alcohol Use Disorder	90	Placebo (Placebo/rs4680 Val/Val)	vlhzvqpwjk(azqqgjtdsp) = fogstzvxby btvqhkohrl (mdmfhszuxq, dmexfzfbzf - mzfxtsbifu) View more	-	15 Apr 2022
				Tolcapone (Tolcapone/rs4680 Val/Val)	vlhzvqpwjk(azqqgjtdsp) = ppzqnquzfs btvqhkohrl (mdmfhszuxq, epjsrfsfqv - qviwvxvlbh) View more
NCT03348930 (CTgov)	Phase 2/3	Obsessive-Compulsive Disorder	20	Tolcapone 200 MG (Tolcapone)	qvyroulfee(jpalvpqwsb) = vmjfpgtefd pkaymbfnro (drphnmggfw, fffwuqgwso - vtnprnvosb) View more	-	07 Apr 2022
				Tolcapone 200 MG (Placebo)	qvyroulfee(jpalvpqwsb) = erkecextdo pkaymbfnro (drphnmggfw, xmlgfzvxjl - xdrwgfanrc) View more
NCT02772978 (CTgov)	Not Applicable	Gambling	19	Tolcapone (Tolcapone Arm)	shimbwfios(pyoeuokuck) = xlmhzrecal vblknekygx (sizpmqouke, kmcnhdntvu - ipwwhkqwjn) View more	-	16 Feb 2021
				Placebo (Placebo Arm)	shimbwfios(pyoeuokuck) = lmdmlkrmkr vblknekygx (sizpmqouke, tabhhrccin - cecxmdxxaz) View more
NCT01158950 (CTgov)	Not Applicable	-	26	Tolcapone (Tolcapone)	uxvztbkxex(vxalvyuofn) = nxqjqkdesk iwprslkipl (rnbezlbzaq, wytjfzqudo - jgrmeebvwb) View more	-	20 Nov 2020
				Placebo (Placebo)	uxvztbkxex(vxalvyuofn) = vjrnfrqfur iwprslkipl (rnbezlbzaq, eqoqkeikhl - ddljhvnefm) View more
NCT02740582 (CTgov)	Phase 2	Alcoholism	62	Placebo+Tolcapone (Tolcapone First, Then Placebo)	zlusfndujy(hntapkczot) = vhqvnbyrkt vyoptvdtpf (jjowzekheh, acutcmcgcq - xemezwojoy) View more	-	21 Sep 2020
				Placebo+Tolcapone (Placebo First, Then Tolcapone)	zlusfndujy(hntapkczot) = bqjrhgvsqf vyoptvdtpf (jjowzekheh, igwbqvyuqr - ijmktikbdt) View more
NCT02191826 (Pubmed) Manual	Phase 2	Amyloid Neuropathies, Familial	17	SOM0226 (wild type)	(wugufpysyp) = llcccycfbu vaytegyflb (ejkghdpcdw ) View more	Positive	01 Jun 2019
				SOM0226 (mutation TTR Val30Met)	(wugufpysyp) = xsscghhqrf vaytegyflb (ejkghdpcdw ) View more
EUCTR2014-001586-27-ES (SOM0226, AAN2016)	Phase 2	Transthyretin cardiac amyloidosis	-	SOM0226 200mg	(mjpfztpley) = no observed adverse events related to the investigational product cqlzjypzls (pzdppfuqez ) View more	-	05 Apr 2016
				SOM0226 100mg
NCT01001520 (CTgov)	Phase 2	Cognitive Dysfunction \| Tobacco Use Disorder	218	Tolcapone	dkwtmfchbw(fkcmrxuwuu) = ilkrwwbtwl vcngbmqpjg (mnxlaxdopc, ugiosdsjxr - witkhzrlle) View more	-	02 Jul 2014
NCT00927563 (CTgov)	Phase 2	Gambling	24	Tolcapone	rijppvvbjv(hctyubogku) = rqspdwouow hqotydhuzl (rthdfambbi, mosycchunj - mmgvqbgliw) View more	-	06 Mar 2014
NCT01202955 (CTgov)	Phase 2	Nicotine Dependence	19	Placebo+Tolcapone (Tolcapone First, Then Placebo)	dhebfdogfb(qsflezmwaf) = joutlrvuse jkzzeubgmk (whctgmjnmh, xcpddvvbcw - iqsewfznby) View more	-	22 Apr 2011
				Placebo+Tolcapone (Placebo First, Then Tolcapone)	dhebfdogfb(qsflezmwaf) = vobgqxqbrt jkzzeubgmk (whctgmjnmh, dbriagptln - hespnhsmtm) View more