CS27109, A Selective Thyroid Hormone Receptor-beta Agonist Alleviates Metabolic-Associated Fatty Liver Disease in Murine Models

Background/Aim. Thyroid hormone receptor-beta (THR-beta) agonists play crucial roles in dyslipidemia and metabolic associated fatty liver disease (MAFLD). We developed a novel oral and liver-targeted THR-beta agonist, CS27109, and evaluated its efficacy in the treatment of metabolic disorders. Materials and Methods. We evaluated in vitro and in vivo efficacy and/or safety of CS27109 along with MGL3196 (a phase III THR-beta agonist). Results. CS27109 showed pronounced activity and selectivity to THR-beta and favorable PK properties, which was equivalent to MGL3196. In the hamster model, animals treated with a high dose of CS27109 showed equivalent reductions in serum TC and LDL-c with groups treated with MGL3196. In the rat model, CS27109 and MGL3196 reduced serum ALT, TC, TG, LDL-c, liver weight ratio, and liver steatosis. CS27109 simultaneously decreased liver TG and TC, and MGL3196 additionally reduced AST. In the mouse model, CS27109 dose-dependently reduced serum AST, ALT, liver inflammation, and NAS score, and also downregulated TC, LDL-c, liver steatosis, and fibrosis, but not in a dose-dependent manner. MGL3196 revealed an equivalent effect with CS27109 in that model. CS27109 also exhibited tolerable toxicity to the heart. Conclusions. CS27109 shows comparative in vitro and in vivo efficacy with MGL3196, suggesting its potential therapeutic application in the treatment of MAFLD such as dyslipidemia and steatohepatitis.