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.
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Authors | Liuyu Hu, Yipei Gu, Ju Liang, Mengmeng Ning, Junli Yang, Yi Zhang, Hui Qu, Yaxi Yang, Ying Leng, Bing Zhou |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 66
Issue 5
Pg. 3284-3300
(03 09 2023)
ISSN: 1520-4804 [Electronic] United States |
PMID | 36799411
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Thyroid Hormone Receptors beta
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Topics |
- Humans
- Non-alcoholic Fatty Liver Disease
(drug therapy, pathology)
- Thyroid Hormone Receptors beta
- Liver
(pathology)
- Inflammation
(pathology)
- Liver Cirrhosis
(pathology)
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