Delving into the Latest Updates on Sobetirome with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Sobetirome (USAN)

+ [1]

Target

THR-β

Mechanism

THR-β agonists(Thyroid hormone receptor beta-1 agonists)

Therapeutic Areas

Respiratory DiseasesOther Diseases

Active Indication

Idiopathic Pulmonary Fibrosis

Inactive Indication

AdrenoleukodystrophyCOVID-19Lipid Metabolism Disorders+ [1]

Originator Organization

University of California

Active Organization

Yale University

Inactive Organization

Oregon Health & Science University

NeuroVia, Inc.

QuatRx Pharmaceuticals Co.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC20H24O4

InChIKeyQNAZTOHXCZPOSA-UHFFFAOYSA-N

CAS Registry211110-63-3

Thyroid hormone (TH) and it most active form triiodothyronine (T3) are crucial in promoting mitochondrial biogenesis and maintaining cellular homeostasis during the stress response, but their role in paraquat (PQ)-induced pulmonary fibrosis isunclear. The aim of this study was to examine whether there was a deficiency of TH in mouse lung tissue after PQ administration, and to explore the effect of T3, and potential mechanisms of action, in alleviation of PQ-induced pulmonary fibrosis. We found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in the lungs of patients with pulmonary fibrosis than in controls. The expression of DIO2 in lung tissue of PQ injured mice was significantly increased compared to controls (P < 0.001), while the serum T3 level was significantly reduced, compared to the control group (P < 0.001). T3 nebulization significantly improved PQ-induced pulmonary fibrosis in mice, possibly by activating thyroid hormone receptor beta (THRβ). T3 and sobetirome, a specific THRβ agonist significantly upregulated peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC1α) expression, and NH-3 (an antagonist of the thyroid hormone receptor), a THRβ-specific antagonist, significantly inhibited (P < 0.0001) the beneficial effects of T3 on the PQ-induced mitochondrial apoptotic pathway in an epithelial cell line, in vitro. T3 via the THRβ / PGC1α pathway protected against PQ induced pulmonary fibrosis, furnishing a scientific basis for further research on T3 and this pathway could offer a potential novel therapeutic strategy for treating PQ poisoning in humans.

01 Nov 2024·Aquatic Toxicology

Testing the sensitivity of the medaka Transgenic Eleuthero-embryonic THYroid-Specific assay (TETHYS) to different mechanisms of action

Article

Author: Tindall, Andrew J. ; Lemkine, Gregory F. ; Tindall, Andrew J ; Robin-Duchesne, Barbara ; Lemkine, Gregory F ; Pasquier, et David Du ; Sachs, Laurent M. ; Pesce, Elise ; Sachs, Laurent M ; Benitez-Gonzalez, Jessica ; Pasquier, Et David Du

There are many concerns about the impacts of Endocrine-Disrupting Chemicals on both wildlife and human populations. A plethora of chemicals have been shown to interfere with the Hypothalamic-Pituitary-Thyroid (HPT) axis in vertebrates. Disruption of the HPT axis is one of main endocrine criteria considered for the regulation of chemicals, along with the estrogen axis, androgen axis and steroidogenesis (EATS). In response to these concerns, the Organization for Economic Cooperation and Development (OECD) initiated the validation of test guidelines (TGs) covering the EATS modalities. Regarding thyroid activity and/or disruption assessment, three OECD TGs are validated, all of them using amphibians. To date, no OECD TGs based on fish are available for the detection of Thyroid Active Chemicals (TACs). To fill this gap, we developed a new test for the detection of TACs, the TETHYS assay (Transgenic Eleuthero-embryonic THYroid-Specific assay). This assay uses a medaka (Oryzias latipes) transgenic line Tg(tg:eGFP) expressing Green Fluorescent Protein in the thyroid follicles, under the control of the thyroglobulin promoter. This assay is performed at eleuthero-embryonic life-stages with an exposure length of 72 h. In the present study, the following reference chemicals with known thyroid hormone system mechanism of action have been tested: methimazole, sodium perchlorate, sodium tetrafluoroborate, diclofenac, iopanoic acid, sobetirome, NH-3 and 1-850. Except for the thyroid receptor antagonists, all chemicals tested were identified as thyroid active, modifying the total fluorescence and the size of the thyroid follicles. To investigate the test specificity, we tested three chemicals presumed to be inert on the HPT axis: cefuroxime, abamectin and 17α-ethinylestradiol. All were found to be inactive in the TETHYS assay. This promising New Approach Methodology can serve as a foundation for the development of a new OECD TG in the frame of regulatory assessment of chemicals for thyroid activity.

01 Jan 2024·European Journal of Neuroscience

Sobetirome rescues α‐synuclein‐mediated demyelination in an in vitro model of multiple system atrophy

Article

Author: Schubert, Dirk W ; Himmler, Marcus ; Arnold, Philipp ; Winkler, Jürgen ; Mészáros, Lisa ; Dörje, Frank ; Schneider, Yanni

AbstractMultiple system atrophy (MSA) is a rare and rapidly progressive atypical parkinsonian disorder characterized by oligodendroglial cytoplasmic inclusions containing α‐synuclein (α‐syn), demyelination, inflammation and neuronal loss. To date, no disease‐modifying therapy is available. Targeting α‐syn‐driven oligodendroglial dysfunction and demyelination presents a potential therapeutic approach for restricting axonal dysfunction, neuronal loss and disease progression. The present study investigated the promyelinogenic potential of sobetirome, a blood–brain barrier permeable and central nervous system selective thyromimetic in the context of an in vitro MSA model. Oligodendrocyte precursor cells (OPCs) were obtained from transgenic mice overexpressing human α‐syn specifically in oligodendrocytes (MBP29 mouse line), a well‐described MSA model, and non‐transgenic littermates. mRNA and protein expression analyses revealed a substantial rescue effect of sobetirome on myelin‐specific proteins in control and α‐syn overexpressing oligodendrocytes. Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α‐syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA.

100 Deals associated with Sobetirome

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External Link

KEGG	Wiki	ATC	Drug Bank
D09381	-	-	DB07425

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Adrenoleukodystrophy	Phase 1	RU	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	GB	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	FR	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	UA	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	AU	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Discovery	CO	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Discovery	AR	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Discovery	CL	NeuroVia, Inc.	01 Aug 2018
Obesity	Discovery	US	QuatRx Pharmaceuticals Co.	29 Jan 2008
Lipid Metabolism Disorders	Discovery	US	QuatRx Pharmaceuticals Co.	-