Discovery of Potent and Selective THRβ Agonists Based on an N-Benzoylglycine Scaffold for the Treatment of Metabolic Disorders.

Metabolic disorders, including obesity, dyslipidemia, and metabolic dysfunction-associated steatohepatitis (MASH), pose a growing health burden with limited pharmacological options. Thyroid hormone receptor β (THRβ) is a liver-enriched nuclear receptor that regulates lipid metabolism, mitochondrial function, and energy homeostasis, making it a promising therapeutic target. Guided by structural insights, we designed an N-benzoylglycine scaffold as a new chemotype, which provides selectivity for the THRβ receptor against THRα while preserving key interactions with the arginine-rich positively charged pocket. Conformational restriction was introduced to maintain a near-orthogonal orientation that optimizes ligand insertion and hydrogen-bonding with His435. Among the series, compound 18 (ZG-2585) exhibited potent and selective THRβ activation and favorable pharmacokinetic profiles. In a western-diet-induced metabolic disorder mouse model, oral administration of ZG-2585 improved body weight, hepatic steatosis, and lipid accumulation. These results establish the N-benzoylglycine scaffold as a promising chemotype for developing selective, orally active THRβ agonists for metabolic disorders.