# Benzoxazole Derivatives as Potent FXR and PPARα Dual Agonists With Anti‐Fibrotic and Metabolic Regulatory Effects

## TL;DR

MHY5396, a benzoxazole compound, activates two receptors and reduces fibrosis and metabolic issues in liver and kidney models.

## Contribution

MHY5396 is a novel dual FXR and PPARα agonist with strong anti-fibrotic and metabolic benefits.

## Key findings

- MHY5396 reduces lipid accumulation and liver damage in fibrosis models.
- It suppresses TGFβ-induced fibrosis in hepatic stellate cells and renal fibrosis in mice.
- MHY5396 is well absorbed orally and primarily metabolized by CYP1A2.

## Abstract

Fibrotic disease involves excessive fibrous connective tissue accumulation in organs, leading to dysfunction and irreversible damage. Metabolic alterations can sometimes contribute to fibrosis development. This study aimed to develop dual agonists for farnesoid X receptor (FXR) and peroxisome proliferator‐activated receptor alpha (PPARα), targeting anti‐fibrosis and metabolic regulation. Benzoxazole derivatives were found to potently activate both FXR and PPARα in hepatocytes. Among them, MHY5396 showed the most potent effects with low EC50 values. MHY5396 reduced lipid synthesis and enhanced beta‐oxidation in hepatocytes, decreasing lipid accumulation. It also suppressed TGFβ‐induced fibrosis in hepatic stellate cells. In a methionine/choline‐deficient diet mouse model, MHY5396 reduced lipid accumulation, liver damage, and fibrosis. In a thioacetamide‐induced liver fibrosis model, MHY5396 had an anti‐fibrotic effect comparable to obeticholic acid, a potent FXR agonist. MHY5396 also significantly reduced inflammation and fibrosis in renal cells and a folic acid‐induced renal fibrosis mouse model. Pharmacokinetic studies showed that orally administered MHY5396 was well absorbed (F = 98.6%) and primarily metabolized by hepatic CYP1A2 with negligible urinary excretion. Overall, MHY5396, with dual FXR and PPARα agonist activity, exhibited significant anti‐fibrotic and metabolic regulatory properties in liver and kidney fibrosis models, presenting a novel therapeutic potential for fibrotic diseases.

MHY5396, a benzoxazole derivative, functions as a potent dual FXR and PPARα agonist. It exhibits significant anti‐fibrotic and metabolic regulatory effects, effectively improving liver and kidney fibrosis in experimental models. These findings highlight its potential as a therapeutic candidate for fibrosis and metabolic disorders.