Sobetirome

Sobetirome (3,5-dimethyl-4[(4'-hydroxy-3'-isopropylbenzyl)-phenoxy] acetic acid, also known as GC-1 and QRX-431, is a member of a class of compounds known as selective thyromimetics.It was firstly developed by Thomas Scanlan’s group at the University of California-San Francisco (UCSF) in 1995 ¹.

In cholesterol-fed rats, sobetirome was shown to lower plasma cholesterol in a dose-dependent manner by up to 75% of untreated controls. In hypercholesterolemic mice, sobetirome was failed to induce LDL receptor mRNA expression. In different mouse models, sobetirome and T-0681 were shown to promote bile acid production and biliary sterol secretion. In cynomolgus monkeys, sobetirome was shown to reduce plasma cholesterol in a dose-dependent manner by up to 30%. Both sobetirome and T-0681 were shown to increase hepatic expression of the HDL receptor (scavenger receptor-BI, SR-BI) in animals.

In Phase I clinical trials, Sobetirome was shown to be generally well tolerated at all doses studied and proof of the therapeutic concept of cholesterol lowering was clearly demonstrated ¹.

References:
1. Tancevski I, Demetz E, Eller P. Sobetirome: a selective thyromimetic for the treatment of dyslipidemia. Recent Pat Cardiovasc Drug Discov. 2011 Jan;6(1):16-9.

Sobetirome prodrug esters with enhanced blood-brain barrier permeability.[Pubmed:27707627]

Bioorg Med Chem. 2016 Nov 15;24(22):5842-5854.

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. Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood-brain-barrier (BBB) and we endeavored to increase the BBB permeability of Sobetirome using a prodrug strategy. Ester prodrugs of Sobetirome were prepared based on literature reports of improved BBB permeability with other carboxylic acid containing drugs and BBB permeability was assessed in vivo. One Sobetirome prodrug, ethanolamine ester 11, was found to distribute more Sobetirome to the brain compared to an equimolar peripheral dose of unmodified Sobetirome. In addition to enhanced brain levels, prodrug 11 displayed lower Sobetirome blood levels and a brain/serum ratio that was larger than that of unmodified Sobetirome. Thus, these data indicate that an ester prodrug strategy applied to Sobetirome can deliver increased concentrations of the active drug to the central nervous system (CNS), which may prove useful in the treatment of CNS disorders.

New synthetic routes to thyroid hormone analogs: d6-sobetirome, (3)H-sobetirome, and the antagonist NH-3.[Pubmed:28316349]

Tetrahedron. 2015 Sep 2;71(35):5946-5951.

New synthetic routes for the preparation of isotopically labeled versions of thyroid hormone agonist Sobetirome were developed using Knochel's iodine-magnesium exchange. A more efficient synthesis of the thyroid hormone antagonist NH-3 was developed from a common intermediate in the Sobetirome route. Using the new synthetic routes, d6- and (3)H-Sobetirome were prepared for their use in studying biodistribution and the cellular uptake of Sobetirome. The new route to NH-3 allows for a more rapid and efficient synthesis and provides access to an advanced intermediate to facilitate antagonist analog production in the final bond-forming synthetic step.

Sobetirome: the past, present and questions about the future.[Pubmed:26565124]

Expert Opin Ther Targets. 2016;20(2):145-9.

Sobetirome binds selectively to the main hepatic form of thyroid hormone (TH) receptor, TRbeta1, compared to TRalpha1, 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. Despite the fact that cardiovascular disease remains a major cause of mortality and that new therapies are desperately needed, it is unlikely that Sobetirome will progress in further human clinical trials in the near future. The emergence of alternative cholesterol-lowering therapeutics may render selective thyromimetics redundant. Further, fears of thyrotoxic effects in the heart and emergence of cartilage defects in dogs after long-term use of eprotirome, a similar though not identical compound, has reduced enthusiasm for this strategy. We argue that it is nevertheless important to explore uses of Sobetirome in humans; more treatment strategies would help patients with hard-to-treat dyslipidemias. Sobetirome may also have additional applications in orphan indications and short-term controlled weight loss.

Sobetirome: a selective thyromimetic for the treatment of dyslipidemia.[Pubmed:21208155]

Recent Pat Cardiovasc Drug Discov. 2011 Jan;6(1):16-9.

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 beta-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. In summary, thyromimetics such as Sobetirome may represent a useful treatment for combined hyperlipidemia, which is associated with a major cardiovascular risk.

The thyroid hormone receptor-beta agonist GC-1 induces cell proliferation in rat liver and pancreas.[Pubmed:16574785]

Endocrinology. 2006 Jul;147(7):3211-8.

Thyroid hormones regulate cell growth, cell differentiation, and metabolic functions via interaction with the thyroid hormone nuclear receptors (TRs). Recently, a small class of halogen-free high-affinity thyroid hormone agonists has been developed that are highly selective for the TRbeta subtype. Because of the selective hyperthyroidism generated by one of these agonists, GC-1, this compound has the potential to be developed as a new therapeutic agent for the treatment of a variety of metabolic disturbances, including lipid disorders and obesity; thus, it becomes important to determine whether GC-1 has other unknown effects on potential target organs. The purpose of this study was to investigate the effect of GC-1 on cell proliferation in rat liver and pancreas. Rats treated with GC-1 (50 or 100 mug/100 g body weight) were killed at different time points. Hepatic and pancreatic cell proliferation was monitored by immunohistochemical determination of bromodeoxyuridine incorporation. The expression of cell cycle-related genes was analyzed by Northern and Western analysis. The results show that GC-1 strongly stimulates rat hepatocyte proliferation in the absence of tissue injury. Although GC-1-induced hepatocyte proliferation was associated with a rapid increase in cyclin D1 mRNA levels, no change in the expression of c-jun and c-fos was observed. GC-1 also induced massive pancreatic cell proliferation. The results indicate that the TRbeta-selective agonist GC-1 is a strong mitogen for hepatocytes and pancreatic acinar cells. Furthermore, they suggest that the TRbeta receptor is the mediator for the mitogenic activity of thyroid hormone and other thyromimetics.

Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice.[Pubmed:16006512]

Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10297-302.

Thyroid hormones [predominantly 3,5,3'-triiodo-L-thyronine (T3)] regulate cholesterol and lipoprotein metabolism, but cardiac effects restrict their use as hypolipidemic drugs. T3 binds to thyroid hormone receptors (TRs) alpha and beta. TRbeta is the predominant isoform in liver, whereas T3 effects on heart rate are mediated mostly by TRalpha. Drugs that target TRbeta or exhibit tissue-selective uptake may improve plasma lipid levels while sparing the heart. Here, we asked how the TRbeta- and liver uptake-selective agonist GC-1 influences cholesterol and triglyceride metabolism in euthyroid mice. GC-1 treatment reduced serum cholesterol levels by 25% and serum triglycerides by 75% in chow-fed mice and also attenuated diet-induced hypercholesterolemia. GC-1 reduced plasma high-density lipoprotein cholesterol levels; increased expression of the hepatic high-density lipoprotein receptor, SR-BI; stimulated activity of cholesterol 7alpha-hydroxylase; and increased fecal excretion of bile acids. Collectively, these results suggest that GC-1 stimulates important steps in reverse cholesterol transport. Use of TRbeta and uptake selective agonists such as GC-1 should be further explored as a strategy to improve lipid metabolism in dyslipoproteinemia.

A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor.[Pubmed:9653548]

Chem Biol. 1998 Jun;5(6):299-306.

BACKGROUND: Thyroid hormones regulate many different physiological processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TR alpha and TR beta, and these two TRs are often co-expressed at different levels in different tissues. Most thyroid hormones do not discriminate between the two TRs and bind both with similar affinities. RESULTS: We have designed and synthesized a thyroid hormone analog that has high affinity for the TRs and is selective in both binding and activation functions for TR beta over TR alpha. The compound, GC-1, was initially designed to solve synthetic problems that limit thyroid hormone analog preparation, and contains several structural changes with respect to the natural hormone 3,5,3'-triiodo-L-thyronine (T3). These changes include replacement of the three iodines with methyl and isopropyl groups, replacement of the biaryl ether linkage with a methylene linkage, and replacement of the amino-acid sidechain with an oxyacetic-acid sidechain. CONCLUSIONS: The results of this study show that GC-1 is a member of a new class of thyromimetic compounds that are more synthetically accessible than traditional thyromimetics and have potentially useful receptor binding and activation properties. The TR beta selectivity of GC-1 is particularly interesting and suggests that GC-1 might be a useful in vivo probe for studying the physiological roles of the different thyroid hormone receptor isoforms.