255820-47-4Relevant articles and documents
Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis
Azzara, Anthony V.,Cao, Gary G.,Carpenter, Joseph,Cook, Erica M.,Ellsworth, Bruce Alan,Krupinski, Jack,Mosure, Kathy,Rossi, Karen A.,Sitkoff, Doree,Soars, Matthew G.,Wacker, Dean A.,Wang, Tao,Wang, Ying,Wu, Gang,Zhuo, Xiaoliang,Ziegler, Milinda
, p. 1413 - 1420 (2021)
Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued evaluation.
COMPOSITIONS AND METHODS FOR TREATING LIVER DISORDERS
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Paragraph 0221, (2021/12/31)
The present disclosure is directed to FXR agonists, pharmaceutical compositions thereof, and methods of using the same for preventing, treating, or ameliorating fatty liver diseases such as steatosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, either alone or in combination with thyroid receptor agonists.
Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis
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
, p. 12748 - 12772 (2020/12/17)
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.
