Synthesis and preclinical testing of a selective beta-subtype agonist of thyroid hormone receptor ZTA-261

Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide. We developed a TH analog, ZTA-261, by modifying the existing THRβ-selective agonists GC-1 and GC-24. To determine the THRβ-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated. ZTA-261 is more selective towards THRβ than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T3, a natural TH, as evidenced by similar changes in the expression of TH-induced and lipid metabolism-related genes. The bone, cardiac, and hepatotoxicity of ZTA-261 are significantly lower than those of GC-1. ZTA-261, a highly selective and less toxic THRβ agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism. Nearly 10% of the world’s population suffers from obesity or is overweight. These conditions are closely related to disorders of lipid metabolism, posing significant challenges to individuals and healthcare systems. Thyroid hormone (TH) activates metabolism by binding to specific protein partners, called TH receptors (THRs). There are two types of THRs, THRα and THRβ. THRβ activates lipid metabolism; however, THRα negatively affects the heart, bone, and muscle when TH is in excess. This study developed a drug called ZTA-261 that selectively binds to THRβ. Its administration to mice with induced obesity from a high-fat diet resulted in reduced body fat without any apparent toxicity. Therefore, ZTA-261 is a promising candidate to improve lipid metabolism and address the obesity epidemic. Nambo, Nishiwaki-Ohkawa, Ito, Ariki et al. characterize a novel thyroid hormone analog, ZTA-261. The authors demonstrate a favorable toxicity profile and effects on lipid metabolism in a high fat diet-induced mouse model of obesity.