Discovery of Highly Potent and Selective Thyroid Hormone Receptor βAgonists 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 beta (THR-beta), 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 alpha (THR-alpha) need to be minimized. Herein, we reported the discovery of a series of novel THR-beta 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-beta over THR-alpha 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.

Automated summary

Nonalcoholic steatohepatitis (NASH) is a progressive stage of nonalcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis. Thyroid hormone receptor beta (THR-beta) is emerging as an effective molecular target for NASH treatment, but minimizing adverse effects mediated by thyroid hormone receptor alpha (THR-alpha) is necessary.