Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis
Junyou Li, Junyou Li, Mengqi Liu, Yazhou Li, Dandan Sun, Zhihao Shu, Qian Tan, Shimeng Guo, Rongrong Xie, Lixin Gao, Hong‐Bo Ru, Yi Zang, Hong Liu, Jia Li, Jia Li, Yu Zhou
Abstract
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.