Journal of Medicinal Chemistry p. 12748 - 12772 (2020)
Update date:2022-08-15
Topics:
Li, Junyou
Liu, Mengqi
Li, Yazhou
Sun, Dan-Dan
Shu, Zhihao
Tan, Qian
Guo, Shimeng
Xie, Rongrong
Gao, Lixin
Ru, Hongbo
Zang, Yi
Liu, Hong
Li, Jia
Zhou, Yu
Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.
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