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

Authors :
Li J
Liu M
Li Y
Sun DD
Shu Z
Tan Q
Guo S
Xie R
Gao L
Ru H
Zang Y
Liu H
Li J
Zhou Y
Source :
Journal of medicinal chemistry [J Med Chem] 2020 Nov 12; Vol. 63 (21), pp. 12748-12772. Date of Electronic Publication: 2020 Oct 13.
Publication Year :
2020

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.

Details

Language :
English
ISSN :
1520-4804
Volume :
63
Issue :
21
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
32991173
Full Text :
https://doi.org/10.1021/acs.jmedchem.0c01065