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

Area of Science:

• Pharmacology
• Hepatology
• Nephrology

Background:

• Fibrotic diseases are characterized by excessive fibrous tissue accumulation, leading to organ dysfunction.
• Metabolic dysregulation is increasingly recognized as a contributing factor in fibrosis development.
• Current therapies for fibrotic conditions remain limited, necessitating novel therapeutic strategies.

Purpose of the Study:

• To develop novel dual agonists targeting both farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor alpha (PPARα).
• To investigate the anti-fibrotic and metabolic regulatory effects of these dual agonists in preclinical models of liver and kidney fibrosis.
• To evaluate the therapeutic potential of lead compound MHY5396 for treating fibrotic diseases.

Main Methods:

• Synthesis and screening of benzoxazole derivatives for dual FXR and PPARα agonistic activity.
• In vitro assessment of MHY5396's effects on lipid metabolism and TGFβ-induced fibrosis in hepatocytes and hepatic stellate cells.
• In vivo evaluation of MHY5396 in methionine/choline-deficient and thioacetamide-induced liver fibrosis mouse models, as well as folic acid-induced renal fibrosis mouse model.
• Pharmacokinetic studies to determine absorption, distribution, metabolism, and excretion of MHY5396.

Main Results:

• Benzoxazole derivatives potently activated both FXR and PPARα, with MHY5396 demonstrating the most significant activity.
• MHY5396 reduced hepatic lipid synthesis, enhanced beta-oxidation, and suppressed TGFβ-induced hepatic fibrosis.
• In vivo studies showed MHY5396 effectively reduced liver damage, lipid accumulation, and fibrosis in multiple models, with effects comparable to obeticholic acid in liver fibrosis.
• MHY5396 also exhibited significant anti-inflammatory and anti-fibrotic effects in renal cells and a kidney fibrosis model.
• Pharmacokinetic analysis revealed MHY5396 has excellent oral bioavailability (98.6%) and is primarily metabolized by CYP1A2 with minimal renal excretion.

Conclusions:

• MHY5396, a novel dual FXR and PPARα agonist, demonstrates potent anti-fibrotic and metabolic regulatory effects in both liver and kidney fibrosis models.
• The compound effectively ameliorates key pathological features of fibrosis, including excessive collagen deposition, inflammation, and lipid accumulation.
• MHY5396 presents a promising therapeutic candidate for the treatment of diverse fibrotic diseases, warranting further clinical investigation.