SLU-PP-332 5mg

Introduction to SLU-PP-332

SLU-PP-332 is a synthetic small molecule developed as a potent, non-selective agonist of estrogen-related receptors (ERRs), with the highest potency for ERRα (EC50 = 98 nM), followed by ERRβ (EC50 = 230 nM) and ERRγ (EC50 = 430 nM). First synthesized in the early 2000s at Saint Louis University School of Medicine (hence the “SLU” prefix), it is designed to mimic the metabolic benefits of aerobic exercise by activating ERR-mediated pathways without estrogenic effects. SLU-PP-332 is primarily studied as an exercise mimetic, with potential applications in obesity, type 2 diabetes (T2D), metabolic syndrome, and neurodegenerative diseases due to its ability to enhance mitochondrial function and energy expenditure.

Preclinical studies in mouse models (e.g., diet-induced obese and ob/ob mice) have demonstrated that SLU-PP-332 increases fatty acid oxidation, reduces fat mass, improves insulin sensitivity, and enhances exercise endurance by up to 70%. It is not approved by regulatory bodies like the FDA or EMA for human use, as it remains in the preclinical stage, with no human clinical trials completed as of 2025. Its use is restricted to laboratory research, and ongoing studies aim to optimize its structure for potential oral administration and evaluate long-term safety.

How SLU-PP-332 Works

SLU-PP-332 activates ERRα, ERRβ, and ERRγ, nuclear receptors that regulate metabolic processes in high-energy-demand tissues like skeletal muscle, liver, heart, and brain. Unlike estrogen receptors, ERRs are “orphan” receptors with no known endogenous ligand, and SLU-PP-332’s hydrazone linkage and Z-configuration at the C=N double bond optimize its binding to the ERR ligand-binding domain. Upon binding, SLU-PP-332 triggers several downstream pathways:

• Mitochondrial Biogenesis: Upregulates TFAM (mitochondrial transcription factor A), increasing mitochondrial density (up to 1.8-fold in skeletal muscle) and enhancing oxidative phosphorylation (OXPHOS).

• Fatty Acid Metabolism: Increases expression of CPT1 (carnitine palmitoyltransferase 1) and MCAD (medium-chain acyl-CoA dehydrogenase), promoting fatty acid uptake and β-oxidation, which shifts metabolism toward fat utilization.

• Glucose Metabolism: Enhances GLUT4 (glucose transporter type 4) expression and AMPK (AMP-activated protein kinase) signaling, improving glucose uptake and insulin sensitivity.

• Exercise-Mimetic Effects: Induces DDIT4 (DNA damage-inducible transcript 4) and Pdk4 (pyruvate dehydrogenase kinase 4), mimicking aerobic exercise by increasing oxidative muscle fibers (Type IIa) and endurance.

In preclinical studies, SLU-PP-332 (50 mg/kg twice daily for 12–28 days in mice) increased energy expenditure, reduced fat mass, and improved glucose tolerance in models of obesity and metabolic syndrome. It also enhanced running capacity by 45–70% in sedentary mice, attributed to increased mitochondrial respiration in C2C12 myocytes and reprogramming of muscle fiber types toward oxidative phenotypes. Pharmacokinetic data indicate moderate oral bioavailability (F ≈ 45%) and high distribution to metabolically active tissues (liver, muscle, adipose), with metabolism primarily via hepatic CYP450 enzymes.

Benefits of Using SLU-PP-332

SLU-PP-332’s potential benefits, based on preclinical studies in mouse models and in vitro research, include:

• Weight Loss and Fat Reduction: Reduces fat mass accumulation in diet-induced obese and ob/ob mice without affecting appetite or requiring physical activity, achieving up to 18% body weight loss over 28 days at 50 mg/kg twice daily.

• Improved Insulin Sensitivity: Enhances glucose tolerance and insulin signaling, reducing blood insulin levels and improving metabolic parameters in models of T2D and metabolic syndrome.

• Enhanced Exercise Endurance: Increases oxidative muscle fibers and mitochondrial density, improving running capacity by 45–70% in sedentary mice, offering potential for studying muscle function in aging or sedentary populations.

• Mitochondrial Function: Boosts cellular respiration and ATP production in skeletal muscle cell lines (e.g., C2C12 myocytes), supporting metabolic efficiency and energy expenditure.

• Cardioprotective Effects: Preserves cardiac contractility in models of heart failure and ischemia-reperfusion injury, suggesting potential for cardiovascular research.

• Potential Neuroprotection: Preliminary studies indicate applications in Alzheimer’s and Parkinson’s diseases by improving mitochondrial function in neuronal cells, though evidence is limited.

• Kidney Protection: Indirectly supports renal health by improving metabolic parameters linked to T2D, potentially reducing kidney stress in obesity-related conditions.

Limitations include the lack of human clinical trials, a short half-life (~1.5 hours), and potential side effects (e.g., mild increases in heart rate or liver enzyme levels), which require further investigation. The compound’s non-selective ERR activation may also pose risks of off-target effects in long-term use.

Certificate of Analysis

SLU-PP-332 5mg – COA – FYP

The following technical details outline the properties of SLU-PP-332 5mg, based on available data.