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

Molecular FormulaC20H24O4

InChIKeyQNAZTOHXCZPOSA-UHFFFAOYSA-N

CAS Registry211110-63-3

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.

28 Oct 2023·Journal of Microbiology and Biotechnology

Comprehensive Evaluation System for Post-Metabolic Activity of Potential Thyroid-Disrupting Chemicals

Article

Author: Park, Ho Jin ; Lee, Do Yup ; Moon, Ji Hyun ; Lee, Hong Jin ; Jang, Yurim ; Jeon, Byung Kwan

Endocrine-disrupting chemicals (EDCs) are compounds that disturb hormonal homeostasis by binding to receptors. EDCs are metabolized through hepatic enzymes, causing altered transcriptional activities of hormone receptors, and thus necessitating the exploration of the potential endocrine-disrupting activities of EDC-derived metabolites. Accordingly, we have developed an integrative workflow for evaluating the post-metabolic activity of potential hazardous compounds. The system facilitates the identification of metabolites that exert hormonal disruption through the integrative application of an MS/MS similarity network and predictive biotransformation based on known hepatic enzymatic reactions. As proof-of-concept, the transcriptional activities of 13 chemicals were evaluated by applying the in vitro metabolic module (S9 fraction). Identified among the tested chemicals were three thyroid hormone receptor (THR) agonistic compounds that showed increased transcriptional activities after phase I+II reactions (T3, 309.1 ± 17.3%; DITPA, 30.7 ± 1.8%; GC-1, 160.6 ± 8.6% to the corresponding parents). The metabolic profiles of these three compounds showed common biotransformation patterns, particularly in the phase II reactions (glucuronide conjugation, sulfation, GSH conjugation, and amino acid conjugation). Data-dependent exploration based on molecular network analysis of T3 profiles revealed that lipids and lipid-like molecules were the most enriched biotransformants. The subsequent subnetwork analysis proposed 14 additional features, including T4 in addition to 9 metabolized compounds that were annotated by prediction system based on possible hepatic enzymatic reaction. The other 10 THR agonistic negative compounds showed unique biotransformation patterns according to structural commonality, which corresponded to previous in vivo studies. Our evaluation system demonstrated highly predictive and accurate performance in determining the potential thyroid-disrupting activity of EDC-derived metabolites and for proposing novel biotransformants.

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	CO	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	GB	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	CL	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	FR	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	AR	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	UA	NeuroVia, Inc.	01 Aug 2018
Adrenoleukodystrophy	Phase 1	AU	NeuroVia, Inc.	01 Aug 2018
Obesity	Phase 1	US	QuatRx Pharmaceuticals Co.	29 Jan 2008
Lipid Metabolism Disorders	Phase 1	US	QuatRx Pharmaceuticals Co.	-