NASH Target Development Service for Thyroid Hormone Receptor-β Agonist

Creative Biolabs is dedicating to develop the novel therapeutics for NASH. Thyroid hormone receptor-β agonist significantly decreases hepatic fat in NASH patients, which indicates it may be a potential therapy. We have extensive experience and a high-end platform and state-of-the-art technology in drug discovery. We are confident in providing high-quality products and custom services to better treat NASH.

Introduction of Thyroid Hormone Receptor-β Agonist

Thyroid hormones (THs) are important regulators of many biological processes including basal metabolic rate and lipid metabolism. There are two main types of THs: L-triiodothyronine (T3) and L-thyroxine (T4). They exert their physiological effects by binding to specific nuclear receptors, the thyroid hormone receptors (THR) ɑ and β, which are widely distributed throughout the body. THRβ plays an important role in lipid metabolism and thyroid-stimulating hormone (TSH) suppression, whereas THRɑ is important for the regulation of the heart rate. The beneficial effects of THR activation include lowering low-density lipoprotein cholesterol and reducing systemic obesity. T3, the major active thyroid hormone, is a potent agonist of THRβ receptors and is mainly used for obesity and hypercholesterolemia, but its utility is limited by unacceptable cardiac side effects. To gain the beneficial effects on lipid metabolism and body weight loss, a number of THRβ-selective agonists have been developed. Among these, Sobetirome (GC-1), Eprotirome (KB2115) and Mgl3196 (via3196), Mb07811 (vk2809) have shown improved therapeutic indices in rodents and humans relative to endogenous. Moreover, they have also been proposed for the treatment of other metabolic disorders.

Tab.1 Effects of various THRβ agonists in human trials. (Jakobsson, 2017)

Thyroid Hormone Receptor-β Agonist for NASH Treatment

Hepatic TH signaling plays an important role in the development and progression of nonalcoholic steatohepatitis (NASH). THR activated signaling pathways are important for organogenesis, growth, and differentiation, and have significant effects on energy metabolism, lipid utilization and glucose homeostasis. Hepatic specific TRβ-specific agonist is an effective lipid-lowering drug, which is expected to treat nonalcoholic fatty liver disease and hepatic insulin resistance. Therefore, the synthesis of a number of THRβ-selective thyromimetics was under development due to the observation that most of the desired beneficial effects of T3 are mediated by the activation of the THRβ in metabolically active organs. For example, MB07811, a liver-selective prodrug THRβ agonist, markedly reduces hepatic steatosis and plasma free fatty acid as well as triglycerides. Unlike T3, MB07811 has beneficial effects on lipids without affecting the heart rate and TSH production at the therapeutic dose. It represents a novel class of liver-targeted TR agonists and may provide additional therapeutic benefit to patients with NASH.

Creative Biolabs offers expert consultation on drug discovery strategies and detailed design plans. Working with our global network of technological, scientific and regulatory scientists can provide you with the right expertise in drug development to improve efficiency, productivity, and profitability. Our platform is a cost-effective and effective option for you to accelerate the development of drug targets. If you are interested in our services, please contact us for more details.

Reference

1. Jakobsson, T.; et al. Potential Role of Thyroid Receptor β Agonists in the Treatment of Hyperlipidemia. Drugs. 2017, 77(3): 1-9.