Selective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders

Abstract

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.

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

“…On the other hand, although tafamidis does not seem to exhibit any other activity analog to hormonal molecules, thyromimetics have attracted attention for their therapeutic TH-like effects [ 29 , 30 , 31 , 32 ]. Diverse thyromimetics have been developed to modulate their activity, permeability, and selectivity, without hampering their therapeutic benefits [ 31 , 33 ].…”

“…Diverse thyromimetics have been developed to modulate their activity, permeability, and selectivity, without hampering their therapeutic benefits [ 31 , 33 ]. In particular, a series of thyromimetics specific for TH receptor β (TRβ) demonstrated various advantageous features against neurodegenerative diseases and metabolic disorders, without the severe side effects often mediated by the activation of TH receptor α [ 32 ]. One of the initial thyromimetics designed for this purpose is sobetirome (GC-1) [ 34 ], which exhibited most of the beneficial effects of T 3 against obesity and lipid metabolism disorder [ 35 ].…”

Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)

“…These include the farnesoid X receptor agonists, obeticholic acid and cilofexor, as well as the peroxisome proliferator-activated receptor agonists, lanifibranor, pioglitazone, elafibranor, and seladelpar. Thyroid hormone receptors (THRs) represent the third class of nuclear receptors targeted for potential NASH therapy [8,9]. Endogenous thyroid hormones (THs), T4 and T3 (Fig 1A ), are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through binding and activation of THRs [10].…”

Involvement of Thyroid Hormones in Brain Development and Cancer

“…NSCs form a heterogeneous population, with the potential to give rise to both neurons and glial cells, depending on specific signals; for example, SVZ NSCs can generate oligodendroglial precursors (OPCs) after injury [ 175 , 204 ]. This latter effect is mediated by THs [ 226 , 227 ], and probably involves THRβ [ 227 ]. Based on this observation, it has been suggested that the use of THRβ agonists might be of help in the treatment of neurodegenerative disorders involving demyelination, such as multiple sclerosis [ 227 ].…”

“…This latter effect is mediated by THs [ 226 , 227 ], and probably involves THRβ [ 227 ]. Based on this observation, it has been suggested that the use of THRβ agonists might be of help in the treatment of neurodegenerative disorders involving demyelination, such as multiple sclerosis [ 227 ].…”