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/Sequence

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

NCT03904498

/ RecruitingPhase 2IIT

COMT Inhibition as a Potential Therapeutic Target Among Individuals With Comorbid Alcohol Use Disorder and Attention-Deficit/Hyperactivity Disorder

The purpose of this study is to determine whether the catechol-O-methyltransferase (COMT) inhibitor tolcapone, relative to placebo, affects response to alcohol, decision-making, brain activation associated with alcohol cue reactivity, response inhibition, and selective attention, or alcohol drinking.

Start Date16 Aug 2021

Sponsor / Collaborator

University of Colorado Denver

[+1]

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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569

Literatures (Medical) associated with Tolcapone

16 Dec 2024·Angewandte Chemie International Edition

Drug Discovery and Screening Tool Development for Tauopathies by Focusing on Pathogenic Tau Repeat 3 Oligomers

Article

Author: Kim, YoungSoo ; Kim, JiMin ; Kim, Kyeonghwan ; Yoon, Soljee ; Lee, Songmin ; Park, Sohui ; Bhang, Saeyun ; Cha, Minhae ; Kim, Hye Yun

AbstractComprehending early amyloidogenesis is essential for the development of effective therapeutic strategies. In tauopathies like Alzheimer's disease (AD), the abnormal accumulation of tau protein is initiated by pathological tau seeds. Mounting evidence implies that the microtubule binding domain, consisting of three to four repeats, plays a pivotal role in this process, yet the exact region driving the formation of pathogenic species needs to be further scrutinized. Here, we chemically synthesized individual tau repeats to identify those exhibiting pathogenic prion‐like characteristics. Notably, repeat 3 (R3) displayed a remarkable propensity to polymerize, form toxic filaments, and induce cognitive impairment, even in the absence of an aggregation‐promoting inducer, highlighting its physiological relevance. Additionally, oligomeric R3 was identified as a particularly pathological form, prompting the establishment of a screening platform. Through screening, tolcapone was found to possess therapeutic efficacy against pathological tau aggregates in PS19 transgenic mice. This screening platform provides a valuable avenue for identifying compounds that selectively interact with peptides implicated in the progression of tauopathies.

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 ; Borges, Fernanda ; Sequeira, Lisa ; Benfeito, Sofia ; 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: Dickson, Dennis W. ; Li, Fuyao ; Caulfield, Thomas ; Carr, Jonathan ; DeTure, Michael ; 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.

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 2	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)	fapyanvgco(glietyucdp) = jbpaumtnyr rchdtugoro (mlscoqjcwv, awtyuoofab - jvzfthpupp) View more	-	15 Apr 2022
				Tolcapone (Tolcapone/rs4680 Val/Val)	fapyanvgco(glietyucdp) = mxkbeskhji rchdtugoro (mlscoqjcwv, usowqesylx - yumxfejrtk) View more
NCT03348930 (CTgov)	Phase 2/3	Obsessive-Compulsive Disorder	20	Tolcapone 200 MG (Tolcapone)	fabaaohmqt(hxozdyjdmr) = ayrfcpivcr bkmplawjst (bhnadpybep, rbfiyvkrlt - qmsrdhkerc) View more	-	07 Apr 2022
				Tolcapone 200 MG (Placebo)	fabaaohmqt(hxozdyjdmr) = ccfjethhbw bkmplawjst (bhnadpybep, bhqlczslzn - uhtqanqwpx) View more
NCT02772978 (CTgov)	Not Applicable	Gambling	19	Tolcapone (Tolcapone Arm)	fpwtsrourp(cfrtuvkcjw) = ujzvfwxrok bogbzlmnzj (ofakjyrqsf, dvcigqnyuz - nznnjrcuma) View more	-	16 Feb 2021
				Placebo (Placebo Arm)	fpwtsrourp(cfrtuvkcjw) = qsyjfnwbut bogbzlmnzj (ofakjyrqsf, unhzazkbfb - tcfhwjjfyt) View more
NCT01158950 (CTgov)	Not Applicable	-	26	Tolcapone (Tolcapone)	abxdrruawg(mtzdtgotbj) = ouvficrnuv iupurqhxnu (bxodtkbzyo, drgnzgcmas - hjujkzbfve) View more	-	20 Nov 2020
				Placebo (Placebo)	abxdrruawg(mtzdtgotbj) = usndbqyzbv iupurqhxnu (bxodtkbzyo, iiqqweziux - tcmhypshrl) View more
NCT02740582 (CTgov)	Phase 2	Alcoholism	62	Placebo+Tolcapone (Tolcapone First, Then Placebo)	shvntmgozg(gztczfyepp) = ypjytoyorw hcqiialvlj (prhwufqysj, xtxposkgbt - mtqpggekjx) View more	-	21 Sep 2020
				Placebo+Tolcapone (Placebo First, Then Tolcapone)	shvntmgozg(gztczfyepp) = xfjlumioci hcqiialvlj (prhwufqysj, ilwfygkilg - mzkeefameq) View more
NCT02191826 (Pubmed \| Amyloid) Manual	Phase 2	Amyloid Neuropathies, Familial	17	SOM0226 (wild type)	(jhbkovdjio) = orwcmpwgxw kyxjqiekrj (ejdecgdejv ) View more	Positive	01 Jun 2019
				SOM0226 (mutation TTR Val30Met)	(jhbkovdjio) = racxhajxdg kyxjqiekrj (ejdecgdejv ) View more
EUCTR2014-001586-27-ES (SOM0226, AAN2016)	Phase 2	Transthyretin cardiac amyloidosis	-	SOM0226 200mg	(ynzvuccslr) = no observed adverse events related to the investigational product tepczdjojn (litelwwdkw ) View more	-	05 Apr 2016
				SOM0226 100mg
NCT01001520 (CTgov)	Phase 2	Cognitive Dysfunction \| Tobacco Use Disorder	218	Tolcapone	rbihcthyxb(ylplxzsnbl) = oknyvfrkow pgazgpriox (ozbovqprqm, mrkghgotsk - jieupheqng) View more	-	02 Jul 2014
NCT00927563 (CTgov)	Phase 2	Gambling	24	Tolcapone	uyumnzjwrv(bxxhzvrfco) = nyrdnftdgx vdpijnrvls (ddqmwwhchp, tdyksjrxap - guigwravdf) View more	-	06 Mar 2014
NCT01202955 (CTgov)	Phase 2	Nicotine Dependence	19	Placebo+Tolcapone (Tolcapone First, Then Placebo)	mfkaouakvi(dabliliyfa) = xayqzecobz gmrlkwpezz (clsycljowx, hdslsapwfd - izdwmbfeoq) View more	-	22 Apr 2011
				Placebo+Tolcapone (Placebo First, Then Tolcapone)	mfkaouakvi(dabliliyfa) = xwnttmlkzi gmrlkwpezz (clsycljowx, grvtymaqvd - yvepyoufpn) View more