Thyroid hormones (THs) elicit significant effects on numerous physiological processes, such as growth, development, and metabolism. A lack of thyroid hormones is not compatible with normal health. Most THs effects are mediated by two different thyroid hormone receptor (TR) isoforms, namely TRα and TRβ, with the TRβ isoform known to be responsible for the main beneficial effects of TH on liver. In brain, despite the crucial role of TRα isoform in neuronal development, TRβ has been proposed to play a role in the remyelination processes. Consequently, over the past two decades, much effort has been applied in developing thyroid hormone analogs capable of uncoupling beneficial actions on liver (triglyceride and cholesterol lowering) and central nervous system (CNS) (oligodendrocyte proliferation) from deleterious effects on the heart, muscle and bone. Sobetirome (GC-1) and subsequently Eprotirome (KB2115) were the first examples of TRβ selective thyromimetics, with Sobetirome differing from the structure of thyronines because of the absence of halogens, biaryl ether oxygen, and amino-acidic side chain. Even though both thyromimetics showed encouraging actions against hypercholesterolemia, non-alcoholic steatohepatitis (NASH) and in the stimulation of hepatocytes proliferation, they were stopped after Phase 1 and Phase 2–3 clinical trials, respectively. In recent years, advances in molecular and structural biology have facilitated the design of new selective thyroid hormone mimetics that exhibit TR isoform-selective binding, and/or liver- and tissue-selective uptake, with Resmetirom (MGL-3196) and Hep-Direct prodrug VK2809 (MB07811) probably representing two of the most promising lipid lowering agents, currently under phase 2–3 clinical trials. More recently the application of a comprehensive panel of ADME-Toxicity assays enabled the selection of novel thyromimetic IS25 and its prodrug TG68, as very powerful lipid lowering agents both in vitro and in vivo. In addition to dyslipidemia and other liver pathologies, THs analogs could also be of value for the treatment of neurodegenerative diseases, such as multiple sclerosis (MS). Sob-AM2, a CNS- selective prodrug of Sobetirome has been shown to promote significant myelin repair in the brain and spinal cord of mouse demyelinating models and it is rapidly moving into clinical trials in humans. Taken together all these findings support the great potential of selective thyromimetics in targeting a large variety of human pathologies characterized by altered metabolism and/or cellular differentiation.
Thyroid hormones (THs), namely 3,3′,5,-triiodo-L-thyronine (T3), 3,3′,5,5′-tetraiodo-L-thyronine (T4) and their metabolites refer to a group of tyrosine-based molecules rich in iodine, which exert a key regulatory role in human metabolism. Indeed, THs are involved in fetal tissues differentiation, brain development, cardiovascular homeostasis, skeletal maintenance, and in the control of carbohydrates and lipids metabolism. Thyroxine (T4) is the prevalent form of TH, produced and released from the thyroid gland in humans. Once released, T4 is converted into T3, the major form of TH, by two enzymes called deiodinases type I (D1) and type II (D2), whereas type III deiodinases (D3) leads to the formation of reverse T3 (rT3), that represents a key step in the process of TH inactivation. This classical picture in the last decade turned to be simplistic, since different classes of enzymes, namely deiodinases, amine transferases, amine oxidases, decarboxylase, and sulfotransferases, have been demonstrated to act on T4 and T3. As a matter of facts, several derivative metabolites of T4 and T3, active on THs receptors, are produced and identified as novel thyroid hormones. These are 3,5-didiodothyronine (T2); thyronamines, particularly 3-iodothyronamine (T1AM) and non-iodinated thyronamines (T0AM); thyroacetic acids, particularly 3,5,3′,5′-thyroacetic acid (TA4), 3,5,3′-thyroacetic acid (TA3), 3-thyroacetic acid (TA1), which will be not discussed in details in this review.
During the past few decades, increasing interest has been directed toward a possible therapeutic use of THs and their analogs in the field of dyslipidemia and liver diseases, with an abundance of data coming from many new promising compounds. Initially the idea that thyromimetics could be useful in lipid metabolism came from the clinical observation that patients with hyperthyroidism show an important reduction of body weight and serum cholesterol. Unfortunately, they also suffer from many unwanted secondary effects such as cardiovascular impairment, muscle and bone loss and depression. Thus, the potential to uncouple the beneficial effects of THs from side effects offers an intriguing challenge.
THs actions can be mediated by THs receptors (TRs) or not, leading to a wide range of effects, previously described as genomic and non-genomic effects. Recently a revision of this over simplified description has been proposed with a novel classification of THs effects according to the involved molecular pathways, as reported in the next paragraph. THs receptors (TRs) have been known since 1986. They are part of a larger family of intracellular receptors that includes those for steroid hormones, retinoic acid, vitamin D, and peroxisomal proliferators. TRs act as transcriptional factors that regulate a wide variety of genes through the interaction with specific co-activators, co-repressors and DNA sequences (TH response elements—TREs), located in the regulatory regions of target genes.
The two isoforms TRα and TRβ are encoded by two genes, THRA on chromosome 17 and THRB on chromosome 3 in human species (Thra and Thrb in mice), respectively, and various forms of TR proteins are produced, through alternative splicing. The distribution of specific isoforms varies between different tissues and species: in human, TRα is proved to be predominant in the heart, brain and bone, whereas TRβ is prevalent in the liver, kidneys, pituitary gland, and brain, and it is responsible for THs effects on metabolism. Based on this consideration, in the last few decades considerable effort has been devoted to developing compounds endowed of selectivity for the beta isoform of the TRs, that would be effective on the treatment of metabolic and/or on brain disorders, without producing deleterious effects on heart and bone. To date, several molecules have been developed, including Sobetirome (GC-1) and Eprotirome (KB2115), just to mention two compounds that have been extensively investigated for many years. These molecules showed great promise of becoming drugs for the treatment of lipid metabolism disorders, but ultimately failed to reach the therapeutic market because of the onset of unwanted side-effects. Noteworthy, in recent years there has been a resurgence of interest in developing TRβ selective thyromimetics, and in particular “tissue-selective prodrugs” able to release the desired active compound at the site of action. The aim of the present review is to provide an update regarding the most significant steps toward the obtainment of clinically useful thyromimetics, providing further details on a subject that has already been widely discussed in recent reviews.
In the liver, THs are actively involved in the regulation of metabolism throughout different pathways. Indeed, THs increase energy expenditure by having a direct effect on ATP consumption in metabolic cycles and membrane permeability as well as by indirect effects on mitochondrial biogenesis and activation. In addition, different critical steps in the lipid metabolism are under THs control: cholesterol serum clearance by the low density lipoprotein (LDL) receptor, 3-hydroxy-3-metylgutaryl-coenzyme A reductase, cholesterol biosynthesis and cholesterol 7α-hydroxylase (CYP7A1). Disruption in the normal THs signaling has been also reported to be causative of liver diseases such as non-alcoholic fatty liver disease (NAFLD), a very common disease in Western countries, whereas exogenous T3 administration has been demonstrated to improve the fatty profile in animals with experimental induced NAFLD. Finally, neoplastic process in the liver as hepato-carcinoma (HCC) appears to be correlated with THs signaling alterations and some studies demonstrated T3 to be effective in reducing cancer progression and metastasis formation. Overall, THs appear significantly beneficial for the liver metabolism. Unfortunately, these positive effects are accompanied by the dangerous effects of thyrotoxicosis, such as tachycardia, muscle wasting, bone impairment, in addition to harmful effects in the brain.
Many studies in animal models underlined the importance of TRs for the specific action of THs in the liver. THs have been demonstrated to regulate 7α-hydroxylase (CYP7A), a crucial liver enzyme in the synthesis of bile acids. TRα1 and TRβ different contribution to this regulation has been studied in TRα1 and TRβ knockout mice treated with 2% dietary cholesterol and T3. The study showed that only TRβ knockout mice were unable to modulate CYP7A1 and that T3 administration was not effective on cholesterol levels in these animals, thus suggesting a crucial and specific role of TRβ in liver.
Moreover, this specific role is likely not only dependent on the abundance of TRβ isoform in the liver (which represents the 80% of T3 binding activity in rodent). A distinct zonal expression of the TRs and their respective target genes has been proposed in support of the hepatic target gene specificity by TRs. On the other hand, TRα1 is predominant in the myocardium, where it covers 40 −70% of T3 heart-binding capacity, depending on the species, and it is responsible for the heart side effects of THs excess.
THs play a very critical role on the central nervous system (CNS) as it is depicted by the severe effects on neuropsychological, cognitive development, and motor activity of children with congenital hypothyroidism, a condition known as cretinism.
