2. Academic Validation
  3. Discovery of Highly Potent and Selective Thyroid Hormone Receptor β Agonists for the Treatment of Nonalcoholic Steatohepatitis

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

  • J Med Chem. 2023 Mar 9;66(5):3284-3300. doi: 10.1021/acs.jmedchem.2c01669.
Liuyu Hu 1 2,  Yipei Gu 1,  Ju Liang 2 3,  Mengmeng Ning 1,  Junli Yang 1 4,  Yi Zhang 2 3,  Hui Qu 1,  Yaxi Yang 1 2 5,  Ying Leng 1 3,  Bing Zhou 1 2 5 3 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 3 University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, P. R. China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 36799411 DOI: 10.1021/acs.jmedchem.2c01669
Abstract

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.

Figures
Products