Synthesis and preliminary pharmacological characterization of novel fibrate derivatives as PPAR agonists for the prospective management of metabolic dysfunction-associated disorders

Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly prevalent conditions, largely driven by poor dietary habits and physical inactivity. They share several pathological mechanisms and clinical features, and often co-occur as the disease progresses. A key common factor is insulin resistance, which contributes to liver damage, inflammation, and fibrosis. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play a central role in regulating energy homeostasis and insulin signaling in the liver, skeletal muscle, and adipose tissue. They also influence inflammatory and fibrotic pathways. The three main PPAR isoforms have distinct biological functions: PPARα regulates lipid metabolism and energy expenditure; PPARβ/δ exerts anti-inflammatory effects and enhances glucose uptake in muscle while PPARγ improves insulin sensitivity and reduces hepatic fibrosis. Due to these roles, PPARs are considered promising therapeutic targets for metabolic dysfunction-associated steatohepatitis (MASH). While selective PPAR agonists are already approved for treating hypertriglyceridemia (PPARα) and type 2 diabetes (PPARγ), their efficacy in MASH has shown mixed results. However, pan-PPAR agonists—which activate all three isoforms—such as lanifibranor, have demonstrated encouraging outcomes in phase II clinical trials, improving both liver and cardiometabolic health. In this context, our research group has long been engaged in the synthesis and biological evaluation of novel compounds with multi-target activity on PPAR receptors.4 Here, we report the synthesis and preliminary assessment of PPAR agonist activity, via transactivation assays, of a new series of fibrate-related ligands targeting all three PPAR isoforms.