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Guoying Yu, Argyris Tzouvelekis, Rong Wang, Jose D Herazo-Maya, Gabriel H Ibarra, Anup Srivastava, Joao Pedro Werneck de Castro, Giuseppe DeIuliis, Farida Ahangari, Tony Woolard, Nachelle Aurelien, Rafael Arrojo E Drigo, Ye Gan, Morven Graham, Xinran Liu, Robert J Homer, Thomas S Scanlan, Praveen Mannam, Patty J Lee, Erica L Herzog, Antonio C Bianco, Naftali Kaminski
Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonary fibrosis than in control individuals and were correlated with disease severity. We also found that Dio2-knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1)...
January 2018: Nature Medicine
J Matthew Meinig, Skylar J Ferrara, Tania Banerji, Tapasree Banerji, Hannah S Sanford-Crane, Dennis Bourdette, Thomas S Scanlan
The blood-brain barrier (BBB) can be a substantial impediment to achieving therapeutic levels of drugs in the CNS. Certain chemical functionality such as the carboxylic acid is a general liability for BBB permeability preventing significant CNS distribution of a drug from a systemic dose. Here, we report a strategy for CNS-selective distribution of the carboxylic acid containing thyromimetic sobetirome using prodrugs targeted to fatty-acid amide hydrolase (FAAH), which is expressed in the brain. Two amide prodrugs of sobetirome were shown to be efficient substrates of FAAH with Vmax/KM values comparable to the natural endocannabinoid FAAH substrate anandamide...
August 18, 2017: ACS Chemical Neuroscience
Skylar J Ferrara, J Matthew Meinig, Andrew T Placzek, Tapasree Banerji, Peter McTigue, Meredith D Hartley, Hannah S Sanford-Crane, Tania Banerji, Dennis Bourdette, Thomas S Scanlan
Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination...
May 15, 2017: Bioorganic & Medicinal Chemistry
Jordan Devereaux, Skylar J Ferrara, Tania Banerji, Andrew T Placzek, Thomas S Scanlan
Sobetirome is one of the most studied thyroid hormone receptor β (TRβ)-selective thyromimetics in the field due to its excellent selectivity and potency. A small structural change-replacing the 3,5-dimethyl groups of sobetirome with either chlorine or bromine-produces significantly more potent compounds, both in vitro and in vivo. These halogenated compounds induce transactivation of a TRβ-mediated cell-based reporter with an EC50 value comparable to that of T3, access the central nervous system (CNS) at levels similar to their parent, and activate an endogenous TR-regulated gene in the brain with an EC50 value roughly five-fold lower than that of sobetirome...
October 12, 2016: ChemMedChem
Andrew T Placzek, Skylar J Ferrara, Meredith D Hartley, Hannah S Sanford-Crane, J Matthew Meinig, Thomas S Scanlan
There is currently great interest in developing drugs that stimulate myelin repair for use in demyelinating diseases such as multiple sclerosis. Thyroid hormone plays a key role in stimulating myelination during development and also controls the expression of important genes involved in myelin repair in adults. Because endogenous thyroid hormone in excess lacks a generally useful therapeutic index, it is not used clinically for indications other than hormone replacement; however, selective thyromimetics such as sobetirome offer a therapeutic alternative...
November 15, 2016: Bioorganic & Medicinal Chemistry
C S Filgueira, E Nicolov, R L Hood, A Ballerini, J Garcia-Huidobro, J Z Lin, D Fraga, P Webb, O M Sabek, A O Gaber, K J Phillips, A Grattoni
BACKGROUND/OBJECTIVES: Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-β (TRβ)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings...
November 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Jan Lammel Lindemann, Paul Webb
Sobetirome binds selectively to the main hepatic form of thyroid hormone (TH) receptor, TRβ1, compared to TRα1, which is principally responsible for thyrotoxic effects on heart, muscle and bone. Sobetirome also preferentially accumulates in liver. It was originally envisaged that sobetirome could be used to stimulate hepatic pathways that lower cholesterol without harmful side effects and might be used in conjunction with statins. Indeed, sobetirome progressed through preclinical animal studies and Phase I human clinical trials with excellent results and without obvious harmful side effects...
2016: Expert Opinion on Therapeutic Targets
Jacob E McMillan, Anna N Bukiya, Camisha L Terrell, Shivaputra A Patil, Duane D Miller, Alex M Dopico, Abby L Parrill
Large conductance, voltage- and Ca(2+)-gated K(+) (BKCa) channels play a critical role in smooth muscle contractility and thus represent an emerging therapeutic target for drug development to treat vascular disease, gastrointestinal, bladder and uterine disorders. Several compounds are known to target the ubiquitously expressed BKCa channel-forming α subunit. In contrast, just a few are known to target the BKCa modulatory β1 subunit, which is highly expressed in smooth muscle and scarce in most other tissues...
November 2014: Journal of Molecular Graphics & Modelling
A G Unnikrishnan, Manash Baruah, Sanjay Kalra
Thyromimetic agents that can treat dyslipidemia without adverse effects like cardiac arrhythmias and osteoporosis are attractive options. Initial experience with desssicated thyroid hormone extract and DT4 were disappointing. Thyroid hormone has nuclear action with four receptor isoforms- TR α1, TRα2, TRβ1, TRβ2. TR α1 has predominant effects on CVS, TRβ2 acts mainly on the pituitary and TRβ1 has hepatoselective action and decrease cholesterol levels. Eprotirome and Sobetirome are 2 thyromimetics that have selective TRβ1 activity...
December 2012: Indian Journal of Endocrinology and Metabolism
Ivan Tancevski, Egon Demetz, Philipp Eller
Atherosclerosis and its clinical sequelae still represent the primary cause of death in Western societies. During the past 25 years, a novel drug class to treat dyslipidemia, a main risk factor for coronary artery disease, emerged: liver- and thyroid hormone receptor isoform β-selective analogs. The present review will discuss the recent patents applied for sobetirome (GC-1), which set the course for the establishment of a novel approach to lower plasma cholesterol and triglycerides. We will focus on the major mechanisms conferring sobetirome lipid-lowering properties, including the induction of hepatic LDL receptor, the promotion of the so-called reverse cholesterol transport, and finally the induction of bile acid production and biliary sterol secretion...
January 2011: Recent Patents on Cardiovascular Drug Discovery
Federica Cioffi, Antonia Lanni, Fernando Goglia
PURPOSE OF REVIEW: The article is principally intended to describe the recent evolutions in the field of research concerned with the metabolic actions of thyroid hormones and those of some of their metabolites or derivatives. Mitochondria, as a result of their functions, represent the principal objective of scientists investigating the mechanisms underlying the effects of thyroid hormones or their metabolites/derivatives. RECENT FINDINGS: Indeed, some important recent findings concern these organelles, and in particular mitochondrial uncoupling and its modulation by effectors...
October 2010: Current Opinion in Endocrinology, Diabetes, and Obesity
Thomas S Scanlan
Sobetirome, also known as GC-1 and QRX-431, is a member of a class of compounds known as selective thyromimetics (Scanlan et al., Curr Opin Drug Discov Dev 4:614-622). These compounds are synthetic structural analogs of thyroid hormone that have tissue-specific thyroid hormone actions. Many of the compounds in this class, including sobetirome, also are subtype-selective thyroid hormone receptor (TR) agonists. Sobetirome selectively binds to and activates TRbeta over TRalpha and this receptor selectivity led to the hypothesis that sobetirome would lower cholesterol through activation of liver TRbeta without stimulating cardiac function through TRalpha activation in the heart...
March 2010: Heart Failure Reviews
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