Discovery of Highly Potent and Selective Thyroid Hormone Receptor β Agonists for the Treatment of Nonalcoholic Steatohepatitis

Nonalcoholic
steatohepatitis (NASH) is a progressive stage of nonalcoholic
fatty liver disease (NAFLD) and is characterized by steatosis, inflammation,
hepatocyte ballooning, and fibrosis. While there are currently no
approved therapies for NASH, the thyroid hormone receptor β
(THR-β), primarily expressed in the liver, is emerging as an
effective molecular target for the treatment of NASH. However, the
adverse cardiac and bone effects mediated by thyroid hormone receptor
α (THR-α) need to be minimized. Herein, we reported the
discovery of a series of novel THR-β agonists featuring pyrrolo[3,2-b]pyridin-5-one skeletons based on structure-based drug
design. Further optimization led to compound 15, which
exhibited higher potency and selectivity for THR-β over THR-α
compared to clinical drug MGL-3196. More significantly,
an excellent liver-to-serum ratio of 93:1 was observed for compound 15. We believe that the high hepatic concentration of compound 15 may result in no cardiotoxicity.