gc-1-compound and Dyslipidemias

The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and β subtypes of nuclear TH receptors (TRα and TRβ) showed that TRα and TRβ are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRβ selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRβ agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRβ agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3'-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRβ mutations, and interesting results have recently been reported in patients with the Allan-Herndon-Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by β-amyloid or by convulsive agents, but no clinical data are available so far.

Topics: Acetates; Anilides; Animals; Central Nervous System Diseases; Clinical Trials as Topic; Diiodothyronines; Drug Design; Dyslipidemias; Humans; Liver Diseases; Male; Mice; Mutation; Non-alcoholic Fatty Liver Disease; Phenols; Pyridazines; Rats; Signal Transduction; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Thyroid Hormones; Thyronines; Triiodothyronine; Uracil

Topics: Animals; Biomimetic Materials; Dyslipidemias; Humans; Hypothalamo-Hypophyseal System; Organ Specificity; Receptors, Thyroid Hormone; Thyroid Hormones

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

Topics: Acetates; Animals; Bile Acids and Salts; Biomarkers; Cholesterol; Dyslipidemias; Humans; Hypolipidemic Agents; Liver; Molecular Mimicry; Phenols; Receptors, LDL; Thyroid Hormones; Treatment Outcome; Triglycerides

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.. Indeed, some important recent findings concern these organelles, and in particular mitochondrial uncoupling and its modulation by effectors. Traditionally, thyroxine (T4) and tri-iodo-L-thyronine (T3) were the only thyroid hormones considered to have metabolic effects, and they alone were considered for potential as agents that might counteract some important abnormalities such as dyslipidaemias and obesity. Several observations, however, led to a reconsideration of this idea. In recent years, studies dealing with the biological activities of some natural metabolites or structural analogues of thyroid hormones have revealed abilities to ameliorate some major worldwide medical problems, such as artherosclerosis, obesity and cardiovascular diseases. Among natural metabolites, 3,5-diiodothyronine (T2) has been shown to powerfully reduce adiposity and dyslipidaemia and to reverse hepatic steatosis without unfavourable side-effects usually observed when T3 or T4 is used. Examples of synthetic analogues are GC-1 (or sobetirome) and KB2115 (or eprotirome) which show ipolipidaemic and antiaterogenic capacities. Clinical trials are in progress for these last agents.. In view of the above-mentioned actions, some of these compounds are now undergoing clinical trials and may have important implications for clinical practice or researches in the field of both endocrinology and metabolic-related abnormalities such as diabetes and dyslipidaemias.

Topics: Acetates; Adiposity; Anilides; Animals; Atherosclerosis; Cardiovascular Diseases; Clinical Trials as Topic; Diiodothyronines; Dyslipidemias; Energy Metabolism; Fatty Liver; Humans; Lipid Metabolism; Mice; Mitochondria; Obesity; Phenols; Rats; Thyroid Hormones

The aggressive reduction of LDL-cholesterol levels by treatment with statins is a key component of preventive cardiovascular care; however, additional therapies to prevent atherosclerosis and the associated clinical sequelae are still needed. Thyromimetic compounds selective for the liver or for the thyroid hormone receptor isoform beta1 constitute a novel approach for the treatment of dyslipidemia. In preclinical studies, selective thyromimetics significantly reduced plasma cholesterol levels and provided protection from atherosclerosis by upregulating the hepatic LDL receptor and promoting reverse cholesterol transport. Importantly, data from ongoing clinical trials have provided the first evidence that selective thyromimetics may also reduce the levels of plasma cholesterol in humans.

Topics: Acetates; Anilides; Animals; Anticholesteremic Agents; Arteriosclerosis; Atherosclerosis; Biological Transport; Biomimetics; Cholesterol, LDL; Clinical Trials as Topic; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipid Metabolism; Malonates; Molecular Structure; Organophosphonates; Phenols; Phenyl Ethers; Phenylacetates; Propionates; Pyridazines; Receptors, LDL; Thyroid Gland; Thyroid Hormones

Inherited abnormalities in apolipoprotein E (ApoE) or low-density lipoprotein receptor (LDLR) function result in early onset cardiovascular disease and death. Currently, the only curative therapy available is liver transplantation. Hepatocyte transplantation is a potential alternative; however, physiological levels of hepatocyte engraftment and repopulation require transplanted cells to have a competitive proliferative advantage of over host hepatocytes. Herein, we aimed to test the efficacy and safety of a novel preparative regimen for hepatocyte transplantation.. Herein, we used an ApoE-deficient mouse model to test the efficacy of a new regimen for hepatocyte transplantation. We used image-guided external-beam hepatic irradiation targeting the median and right lobes of the liver to enhance cell transplant engraftment. This was combined with administration of the hepatic mitogen GC-1, a thyroid hormone receptor-β agonist mimetic, which was used to promote repopulation.. The non-invasive preparative regimen of hepatic irradiation and GC-1 was well-tolerated in ApoE. Significant hepatic repopulation and the cure of dyslipidemia in this model, using a novel and well-tolerated preparative regimen, demonstrate the clinical potential of applying this method to the treatment of inherited metabolic diseases of the liver.. Hepatocyte transplantation is a promising alternative to liver transplantation for the treatment of liver diseases. However, it is inefficient, as restricted growth of transplanted cells in the liver limits its therapeutic benefits. Preparative treatments improve the efficiency of this procedure, but no clinically-feasible options are currently available. In this study we develop a novel well-tolerated preparative treatment to improve growth of cells in the liver and then demonstrate that this treatment completely cures an inherited lipid disorder in a mouse model.

Topics: Acetates; Animals; Apolipoproteins E; Atherosclerosis; Cholesterol; Disease Models, Animal; Dyslipidemias; Female; Hepatocytes; Hyperlipoproteinemia Type II; Male; Mice; Mice, Inbred C57BL; Phenols

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. 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.

Topics: Acetates; Animals; Cardiovascular Diseases; Cholesterol; Clinical Trials as Topic; Dogs; Dyslipidemias; Humans; Liver; Phenols; Thyroid Hormone Receptors beta

The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.

Topics: Animals; Bone Density; Clinical Trials as Topic; Drug Discovery; Dyslipidemias; Humans; Male; Mice; Mice, Inbred C57BL; Pyridazines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thyroid Hormone Receptors beta; Uracil