| 論文編號: |
|
| 第一作者所在部門: |
|
| 中文論文題目: |
Discovery of a Highly Selective and H435R Sensitive Thyroid Hormone Receptor β Agonist |
| 英文論文題目: |
Discovery of a Highly Selective and H435R Sensitive Thyroid Hormone Receptor β Agonist |
| 作者: |
Qiu Li#, Benqiang Yao#, Shiting Zhao, Zhou Lu, Yan Zhang, Qiuping Xiang, Xishan Wu, Haonan Yu, Cheng Zhang, Junhua Li, Xiaoxi Zhuang, Donghai Wu, Yong Li, Yong Xu |
| 論文出處: |
|
| 刊物名稱: |
Journal of Medicinal Chemistry |
| 年: |
2022 |
| 卷: |
65 |
| 期: |
10 |
| 頁: |
7193-7211 |
| 聯係作者: |
Yong Xu |
| 收錄類別: |
|
| 影響因子: |
8.039 |
| 摘要: |
The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) and TRβ mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the "His-Phe switch" to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound16g, which is a potent TRβ agonist (EC50: 21.0 nM, 85.0% of the maximum efficacy of1) with outstanding selectivity for TRβ over TRα and also effectively activates the TRβH435Rmutant. Then, we developed a highly efficient synthetic method for16g. Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation.16galso showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively,16gis a well-characterized selective and mutation-sensitive TRβ agonist for further investigating its function in treating dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH). |
| 英文摘要: |
|
| 外單位作者單位: |
|
| 備注: |
|
