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Papers of the Week

2020 Oct 13

J Med Chem

Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis.


Li J, Liu M, Li Y, Sun D-D, Shu Z, Tan Q, Guo S, Xie R, Gao L, Ru H, Zang Y, Liu H, Li J, Zhou Y
J Med Chem. 2020 Oct 13.
PMID: 32991173.


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 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.