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Potential Role of Thyroid Receptor ? Agonists in the Treatment of Hyperlipidemia.

ABSTRACT: Thyroid hormones have important effects on cellular development, growth, and metabolism and are necessary for the healthy function of almost all tissues. Hyperthyroid patients with excess thyroid hormone levels experience tachycardia, fatigue, muscle wasting, and osteoporosis. However, although high thyroid hormone levels have adverse effects, efforts have been made to harness the beneficial effects, such as reduced serum low-density lipoprotein (LDL) cholesterol levels, elevated basal metabolic rate, and weight loss. Thyroid hormones interact with nuclear thyroid hormone receptors (TRs), and cholesterol levels are reduced through TR?, whereas extrahepatic adverse actions are primarily connected to TR?. Thus, to develop a useful compound for clinical use, efforts have been focusing on developing compounds with isomer-specific functions based on the structure of thyroid hormones, i.e., thyromimetics that are liver and/or TR? specific. In this short review, we discuss the development of the early thyromimetics that enabled, through modern molecular techniques, the progress towards improved design of TR?-selective thyromimetics. We also address the early promise shown in human clinical trials and the current status of these drugs and other emerging compounds.

SUBMITTER: Jakobsson T

PROVIDER: S-EPMC5613055 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Potential Role of Thyroid Receptor β Agonists in the Treatment of Hyperlipidemia.

Jakobsson Tomas T Vedin Lise-Lotte LL Parini Paolo P

Drugs 20171001 15

Thyroid hormones have important effects on cellular development, growth, and metabolism and are necessary for the healthy function of almost all tissues. Hyperthyroid patients with excess thyroid hormone levels experience tachycardia, fatigue, muscle wasting, and osteoporosis. However, although high thyroid hormone levels have adverse effects, efforts have been made to harness the beneficial effects, such as reduced serum low-density lipoprotein (LDL) cholesterol levels, elevated basal metabolic ...[more]

PMID: 28865063

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Project description: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.

Project description:(1) Background: The cannabinoid 2 receptor (CB2R) is a promising anti-inflammatory drug target and development of selective CB2R ligands may be useful for treating sight-threatening ocular inflammation. (2) Methods: This study examined the pharmacology of three novel chemically-diverse selective CB2R ligands: CB2R agonists, RO6871304, and RO6871085, as well as a CB2R inverse agonist, RO6851228. In silico molecular modelling and in vitro cell-based receptor assays were used to verify CB2R interactions, binding, cell signaling (ß-arrestin and cAMP) and early absorption, distribution, metabolism, excretion, and toxicology (ADMET) profiling of these receptor ligands. All ligands were evaluated for their efficacy to modulate leukocyte-neutrophil activity, in comparison to the reported CB2R ligand, HU910, using an in vivo mouse model of endotoxin-induced uveitis (EIU) in wild-type (WT) and CB2R-/- mice. The actions of RO6871304 on neutrophil migration and adhesion were examined in vitro using isolated neutrophils from WT and CB2R-/- mice, and in vivo in WT mice with EIU using adoptive transfer of WT and CB2R-/- neutrophils, respectively. (3) Results: Molecular docking studies indicated that RO6871304 and RO6871085 bind to the orthosteric site of CB2R. Binding studies and cell signaling assays for RO6871304 and RO6871085 confirmed high-affinity binding to CB2R and selectivity for CB2R > CB1R, with both ligands acting as full agonists in cAMP and ß-arrestin assays (EC50s in low nM range). When tested in EIU, topical application of RO6871304 and RO6871085 decreased leukocyte-endothelial adhesion and this effect was antagonized by the inverse agonist, RO6851228. The CB2R agonist, RO6871304, decreased in vitro neutrophil migration of WT neutrophils but not neutrophils from CB2R-/-, and attenuated adhesion of adoptively-transferred leukocytes in EIU. (4) Conclusions: These unique ligands are potent and selective for CB2R and have good immunomodulating actions in the eye. RO6871304 and RO6871085, as well as HU910, decreased leukocyte adhesion in EIU through inhibition of resident ocular immune cells. The data generated with these three structurally-diverse and highly-selective CB2R agonists support selective targeting of CB2R for treating ocular inflammatory diseases.

Dataset Information

Potential Role of Thyroid Receptor ? Agonists in the Treatment of Hyperlipidemia.

Publications

Potential Role of Thyroid Receptor β Agonists in the Treatment of Hyperlipidemia.

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