Highly potent non-steroidal FXR agonists protostane-type triterpenoids: Structure-activity relationship and mechanism

• Published in: European journal of medicinal chemistry 2019-11, Vol.182, p.111652, Article 111652
• Main Authors: Luan, Zhi-Lin, Huo, Xiao-Kui, Dong, Pei-Pei, Tian, Xiang-Ge, Sun, Cheng-Peng, Lv, Xia, Feng, Lei, Ning, Jing, Wang, Chao, Zhang, Bao-Jing, Ma, Xiao-Chi
• Format: Article
• Language: English
• Subjects: Alisma - chemistry; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Cells, Cultured; Dose-Response Relationship, Drug; Farnesoid X receptor; Hep G2 Cells; Humans; Molecular docking; Molecular Docking Simulation; Molecular Structure; Mutagenesis, Site-Directed; Protostane; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - genetics; Site-directed mutagenesis; Structure-Activity Relationship; Terpenes - chemistry; Terpenes - isolation & purification; Terpenes - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111652

Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1–14) and four known analogues (15–18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1–70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC50 = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology. [Display omitted] •Fourteen new protostane-type triterpenoids were isolated from A. orientale.•The structure-activity relationship of protostanes with FXR was investigated.•Compound 15 displayed potent agonistic activity against FXR (EC50 = 90 nM).•High efficacy of compound 15 against FXR in living cell was confirmed.•Compound 15 had interaction with amino acid residues Arg331 and Ser332 of FXR.