SLU-PP-332

The estrogen-related receptors are orphan nuclear receptors, not receptors for estrogen. Genetic studies show they matter for muscle's capacity for exercise, but ERRα had proved hard to activate with a drug. SLU-PP-332, from Saint Louis University, targets all three ERRs with the highest potency at ERRα, and works well enough in vivo to be used as a research tool [1].

The mouse results are what made it famous. It increased the proportion of oxidative type IIa muscle fibers, and after a week of twice-daily injections sedentary mice ran about 70% longer and 45% further on a treadmill than untreated mice [1]. In mice made obese on a high-fat diet, 28 days of treatment left them about 12% lighter. Untreated mice gained about 5 g of fat over that time and treated mice less than 0.5 g, with no change in food intake or lean mass. Fasting glucose and insulin fell and glucose tolerance improved, but an insulin tolerance test did not change [2]. In lean mice on normal chow, it did not change body weight, glucose tolerance or insulin [2]. In a pressure-overload heart failure model it improved ejection fraction, reduced fibrosis and increased survival, mainly through ERRγ [3]. In 21-month-old mice, eight weeks of treatment reversed age-related albuminuria, podocyte loss, mitochondrial dysfunction and kidney inflammation [4].

The ERRs control genes for mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation and the Krebs cycle [5]. Activating them with SLU-PP-332 set off an acute aerobic exercise program in muscle that depended on ERRα [1]. It induced the exercise gene Ddit4 as strongly as treadmill running or more [5]. In the heart its benefit ran mainly through ERRγ, which drove fatty acid metabolism and mitochondrial function [3].

Chemically it is an acyl hydrazone, designed from the earlier ERRβ/γ agonist GSK4716 using the crystal structure of GSK4716 bound to the ERRγ ligand-binding domain. Swapping an isopropylphenyl group for a naphthalene was predicted to add π-stacking with Phe328, a residue unique to ERRα, and that change gave the jump in ERRα potency while keeping activity at ERRβ and ERRγ [6]. A 2026 structure-activity study mapped which parts of the scaffold control potency and ERRα versus ERRγ activity [7].

The hydrazone linker is also its main chemical weakness. Medicinal chemists treat hydrazides and hydrazones as problematic because they are metabolized quickly and carry toxicity concerns; the parent GSK4716 had a human liver microsomal half-life of 6.4 minutes. A 2026 review from the lab that made the compound concludes that SLU-PP-332 is potent and efficacious but not metabolically stable enough to be a drug candidate without further work, and that the field should move to other scaffolds [6].

There is no human safety data. In the original mouse study, ten days of twice-daily injections caused no overt toxicity: blood counts, electrolytes and creatine kinase (a marker of muscle damage) were normal [1]. Genetically obese ob/ob mice tolerated the twice-daily injections less well, so their study was cut to 12 days [2]. A 2026 systematic review of the animal studies reported no evident toxicity in obesity models, and concluded that clinical trials are needed to establish efficacy and safety in humans [11].

It is not orally bioavailable in mice [5], so oral products sold online may deliver little. Their contents are unverified in any case.

The World Anti-Doping Agency prohibits exercise mimetics and metabolic modulators in sport. Anti-doping laboratories have already mapped SLU-PP-332's metabolites in human liver preparations so they can detect it [10][12].

No interaction studies exist. In human liver preparations it forms six phase I and three phase II metabolites [10], but no study says which enzymes are involved.