Discovery of Quinoline-Based Highly Potent and Selective THRβ Agonists for MASLD Treatment

Abstract

Metabolic-dysfunction-associated steatohepatitis (MASH) is a progressive metabolic liver disease lacking sufficient clinical therapies. Thyroid hormone receptor β (THRβ), a liver-enriched nuclear receptor, is an attractive therapeutic target. Resmetirom, the first FDA-approved THRβ agonist for MASH, achieves clinical efficacy yet suffers from suboptimal THRβ/THRα selectivity restricting its therapeutic window. We used a scaffold-hopping strategy to design and synthesize a novel series of quinoline-based THRβ agonists. Systematic SAR optimization identified compound 24 as a potent, selective THRβ agonist, with an EC50 of 46.07 nM and 34.3-fold THRβ/THRα selectivity. It displayed favorable oral bioavailability (F = 54.1%) and approximately 2-fold higher hepatic exposure than Resmetirom. In animal models, compound 24 ameliorated metabolic dysfunction, reduced hepatic lipid accumulation, and suppressed liver inflammation and fibrosis. No obvious thyroid axis disruption or THRα-mediated cardiotoxicity was observed, and mice tolerated compound 24 up to 100 mg/kg. Overall, compound 24 represents a promising THRβ-selective therapeutic candidate for MASH.