SLU-PP-332

SLU-PP-332 is a synthetic small-molecule compound classified as a potent, non-selective pan-agonist of estrogen-related receptors (ERRs), specifically targeting ERRα, ERRβ, and ERRγ with EC50 values of 98 nM, 230 nM, and 430 nM, respectively, in cell-based cotransfection/reporter assays. Chemically identified as (E)-4-Hydroxy-N′-(naphthalen-2-ylmethylene)benzohydrazide (CAS No. 303760-60-3, molecular formula C18H14N2O2, molecular weight 290.32 g/mol), SLU-PP-332 selectively activates ERRs without engaging classical estrogen receptors (ERα, ERβ), thus avoiding estrogenic side effects.

Developed at Saint Louis University, SLU-PP-332 mimics the metabolic effects of aerobic exercise by enhancing mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation. It activates key metabolic pathways, including AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), while inducing the expression of DDIT4, a regulator of cellular stress response. In preclinical studies, SLU-PP-332 increased mitochondrial respiration in C2C12 myocytes and promoted fast oxidative skeletal muscle fibers (Type IIa) in mice, enhancing exercise endurance in an ERRα-dependent manner.

In mouse models of obesity and metabolic syndrome, SLU-PP-332 (50 mg/kg, intraperitoneal, twice daily) increased energy expenditure, reduced fat mass accumulation, and improved insulin sensitivity without affecting food intake or requiring physical activity. Notable effects include a 12% body weight reduction and tenfold less fat gain in obese mice over a 28-day treatment period. Additionally, SLU-PP-332 shows potential in improving cardiac function in heart failure models by enhancing mitochondrial ultrastructure and upregulating oxidative phosphorylation pathways.

SLU-PP-332 also exhibits anti-inflammatory properties by modulating cytokine production (e.g., IL-6, TNF-α) and may inhibit angiotensin-converting enzyme 2 (ACE2), suggesting potential applications in reducing SARS-CoV-2 entry points in adipose tissue. Its ability to enhance glycogen storage and muscle protein synthesis further supports its role in metabolic optimization and muscle preservation.

Supplied by Evox Biolabs, SLU-PP-332 is available in vials containing 5 mg or 10 mg of the compound, with a purity exceeding 90%, suitable exclusively for research purposes. Currently in preclinical development, SLU-PP-332 is intended for research use only and is not approved for human or clinical applications. Its solubility, stability, and biological activity make it a promising candidate for studying metabolic disorders, including obesity, type 2 diabetes, and heart failure, as well as for exploring exercise-mimetic therapies. For batch-specific data, refer to supplier Certificates of Analysis.

References:

• Billon C, et al. ACS Chem Biol. 2023;18(4):756-771.

• ACS Chemical Biology, 2023; Journal of Pharmacology and Experimental Therapeutics; American Chemical Society presentations.