Design and Evaluation of Conformationally Locked Indole-Carboxylic Acids as Selective THRβ Agonists against MASH.

The activation of thyroid hormone receptor β (THRβ) represents a highly validated therapeutic strategy for metabolic dysfunction-associated steatohepatitis (MASH). Nevertheless, attaining high selectivity for THRβ is crucial to prevent the unintended activation of the cardiotoxic THRα subtype. In this work, we capitalized on the flexibility of the hydrophobic binding pocket of THRβ and synthesized a series of cyclized indole-carboxylic acid derivatives using a conformational restriction strategy. The representative compound 14q exhibited potent THRβ agonism (EC50 = 36 nM) and no discernible activity against THRα, confirming its high functional selectivity. In vitro druggability assessments revealed that 14q possesses excellent metabolic stability across species and favorable oral pharmacokinetics in mice. In a murine MASH model, 14q significantly ameliorated hepatic steatosis, serum biomarkers, and liver gene expression profiles, without observable cardiac toxicity. Overall, these findings suggest that 14q is a promising candidate for the development of selective THRβ-targeted therapies for MASH.