Structure Optimization of 12β-O-γ-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist/Modulator for NASH Therapy

Abstract

The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12β-O-(γ-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure–activity relationship (SAR) and identified the most potent compound, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg·Kg−1) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of 10b extends into the H11–H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12β-alkonate. These findings suggest that 12-glutamyl OA derivative 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH).

Overview of Ursolic Acid Potential for the Treatment of Metabolic Disorders, Autoimmune Diseases, and Cancers via Nuclear Receptor Pathways

“…Celastrol, a distinguished friedelane-type PT, is a Nur77 (NR4A1) nuclear receptor with a potential clinical application in Alzheimer's therapy [41,42]. Notably, oleanolic acid (OA) is one of the most studied oleanane-type PTs with respect to NR modulation, with a multitude of bioactivities against NASH [43][44][45], metabolic disorders [45][46][47], and atherosclerosis [48] via different NR pathways that were recently reviewed [49]. Hedragonic acid, an oleanane-type PT isolated from Celastrus orbicalatus, was identified as a hepatoprotective agent against acetaminophen-induced injury through selective FXR agonism.…”

“…with respect to NR modulation, with a multitude of bioactivities against NASH [43-4 metabolic disorders [45][46][47], and atherosclerosis [48] via different NR pathways that we recently reviewed [49]. Hedragonic acid, an oleanane-type PT isolated from Celastr orbicalatus, was identified as a hepatoprotective agent against acetaminophen-induc injury through selective FXR agonism.…”

Harnessing Oleanolic Acid and Its Derivatives as Modulators of Metabolic Nuclear Receptors

“…In continuation of their work, Fang's group designed and synthesized more OA hybrids with 12β-O-β-aspartyl or 12β-O-γ-glutamyl moiety trying to enhance the affinity of compound 6 towards FXR-LBD as shown for compounds 7-10 [83,84]. The design considered the presence of unoccupied hydrophobic space around the compound 6 terminal chain, thus aimed at using more branched chains.…”

“…This is accompanied by a reduction in mRNA expression of fibrosis marker genes. Collectively, compound 10 is an OA derivative and a promising FXR modulator with NASH and diabetes therapeutic potential [84].…”

Development of Cilofexor, an Intestinally-Biased Farnesoid X Receptor Agonist, for the Treatment of Fatty Liver Disease

“…Modulation of the FXR-FGF19 pathway using FXR agonists [or conceivably antagonists, as discussed in (Wang et al, 2018;Panzitt et al, 2022;Ma et al, 2023)] has emerged as a therapeutic strategy for cholestatic liver diseases (in which increased BA levels are implicated in promoting tissue damage, hepatic inflammation, and fibrosis) (Woolbright and Jaeschke, 2012;Carey et al, 2015;Kowdley et al, 2020), and for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Treatment of cholestatic diseases is limited and there is no approved treatment of NAFLD/NASH.…”