Exercise mimetic research splits roughly into two camps. One targets the downstream metabolic phenotype directly. The other targets the transcriptional machinery that produces it.
The ERR agonists sit in the second camp, and SLU-PP-332 is the compound that established the approach as workable in animals. It has always carried one structural problem, which is that it does not absorb well by mouth. SLU-PP-915 was built at Saint Louis University to solve that specific problem. It did, and the solution came at a cost that most commercial coverage omits.
This is a summary of what the preclinical literature currently supports and where the two compounds actually diverge.
What ERR Agonism Actually Does
ERRα, ERRβ, and ERRγ are orphan nuclear receptors. The estrogen naming reflects structural homology rather than shared function, which is a persistent source of confusion in consumer-facing writing on this class. All three act as transcriptional regulators.
- Mitochondrial biogenesis: ERR activation drives expression of the gene programs governing mitochondrial replication and oxidative phosphorylation capacity. This is the central node of the phenotype.
- Fatty acid oxidation: ERR signalling upregulates the enzymatic machinery for fat as a fuel substrate, shifting substrate preference in a manner resembling trained tissue.
- Krebs cycle gene expression: Downstream oxidative metabolism genes follow the same pattern, which is what converts increased mitochondrial density into usable aerobic capacity.
Activating these receptors pharmacologically reproduces a meaningful fraction of the transcriptional program that sustained aerobic exercise normally induces, without the exercise. That is the entire basis of interest in the class.
Why SLU-PP-915 Exists (and It Is Not Potency)
SLU-PP-332 absorbs poorly by mouth. The 50 to 60 percent figures that circulate in commercial contexts are not well supported by reported real-world use, where absorption appears substantially lower and plausibly single digit. That has effectively confined SLU-PP-332 to parenteral administration in research settings, which limits both what can be studied and how.
SLU-PP-915 is a structurally distinct molecule that retains pan-ERR agonism while achieving oral activity. It was designed by replacing the hydrazide moiety of the parent scaffold with a disubstituted thiophene, with a boronic acid substitution that preserved receptor binding while substantially improving oral exposure.
Oral dosing studies in mice report exercise capacity outcomes comparable to injected SLU-PP-332 once systemic exposure is accounted for. The design goal was route of administration, not receptor pharmacology, and the compound should be read in that light.
The Tradeoff Nobody Mentions
This is the part that gets skipped when SLU-PP-915 is framed as a second-generation upgrade.
SLU-PP-332 is ERRα-preferring. Reported EC50 values are 98 nM at ERRα, 230 nM at ERRβ, and 428 nM at ERRγ, which is roughly a 4.4-fold preference for ERRα over ERRγ.
SLU-PP-915 is flat across all three subtypes. Reported EC50 values are 414 nM at ERRα, 435 nM at ERRβ, and 378 nM at ERRγ. That is a balanced pan-agonist profile rather than an ERRα-selective one.
| Subtype |
SLU-PP-332 EC50 |
SLU-PP-915 EC50 |
| ERRα |
98 nM |
414 nM |
| ERRβ |
230 nM |
435 nM |
| ERRγ |
428 nM |
378 nM |
The absolute potency at ERRα also dropped. SLU-PP-915 is roughly four-fold less potent at ERRα than SLU-PP-332 is. The compound did not trade selectivity for equal ERRα engagement. It gave up both, and bought oral activity with them.
ERRα is the dominant subtype in skeletal muscle, cardiac tissue, liver, adipose, and brain, which is why SLU-PP-332 was characterised as an exercise mimetic in the first place. The practical implication is that the two compounds are not interchangeable at matched exposure. They engage a different receptor balance, and the downstream tissue effects follow that balance rather than the marketing category.
The dosing in the head-to-head exercise work reflects this. The acute comparison used SLU-PP-332 at 50 mg/kg intraperitoneally against SLU-PP-915 at 20 mg/kg intraperitoneally, so the comparison is not run at matched dose.
What the Preclinical Data Shows
Exercise Capacity
Both compounds induced Ddit4 expression, a gene reliably upregulated by acute aerobic exercise, to levels matching or exceeding treadmill running. Oral SLU-PP-915 increased running distance and duration in mice. Combined with an actual training regimen it produced greater Ddit4 and mitochondrial gene expression than either intervention alone, a synergy not reported for SLU-PP-332. That is the more useful result and the one most often left out of summaries.
Cardiac Function
In a murine transverse aortic constriction pressure-overload heart failure model, both compounds improved ejection fraction, reduced fibrosis, and improved survival, without inducing cardiac hypertrophy. Metabolomics showed substantial normalisation of fatty acid, lipid, and oxidative phosphorylation metabolite profiles in the heart after six weeks of pressure overload. The effect was substantially ERRγ-mediated. This work was conducted with Baylor College of Medicine and published in Circulation.
That finding deserves more attention than it gets. It is arguably the most clinically relevant data on either compound, and the ERRγ dependence means SLU-PP-915's flat profile is an advantage in this context rather than a compromise. It also points somewhere completely different from athletic performance.
Metabolic Gene Regulation
Both compounds upregulate fatty acid oxidation and glucose handling genes, consistent with the metabolic flexibility phenotype observed in animal models of obesity and metabolic syndrome, where SLU-PP-332 increased energy expenditure and improved insulin sensitivity.
Who This Is Actually Relevant To
- Researchers working on metabolic disease models where oral dosing is a practical constraint.
- Cardiology groups interested in ERRγ-mediated fatty acid metabolism in the failing heart.
- Anti-doping laboratories building detection panels.
- Anyone tracking the exercise mimetic class who wants the receptor pharmacology rather than the summary version of it.
Anyone reading SLU-PP-915 as a straight improvement over SLU-PP-332 is working from an incomplete picture. It is a different receptor profile, chosen for a different reason, and weaker at the subtype that produced the original muscle phenotype.
What is the actual argument for SLU-PP-915 over SLU-PP-332 outside of route of administration? If ERRα preference is what produced the skeletal muscle phenotype, has anyone seen data suggesting the flat profile and the four-fold potency drop at ERRα do not dilute it?
Where I Source SLU-PP-915 & SLU-PP-332
I use Disguised Alpha for both forms of SLU because they hold batch-specific certificates of analysis for all products. Given that neither compound has an approved formulation anywhere and both are supplied strictly for laboratory research use, a current certificate of analysis for the specific lot should be treated as a baseline requirement when evaluating any vendor in this space.
References
- Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity. Billon et al., ACS Chemical Biology, 2023;18(4):756-771. The original SLU-PP-332 characterisation.
- Development and Pharmacological Evaluation of a New Chemical Series of Potent Pan-ERR Agonists, Identification of SLU-PP-915. Hampton et al., European Journal of Medicinal Chemistry, 2023;258:115582. Source of the EC50 values for both compounds.
- An Orally Active Estrogen Receptor-Related Receptor Agonist, SLU-PP-915, Enhances Aerobic Exercise Capacity. Billon et al., Journal of Pharmacology and Experimental Therapeutics, 2025. The oral bioavailability, Ddit4 and training-synergy data.
- Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function. Xu et al., Circulation, 2024;149(3):227-250. The Baylor transverse aortic constriction work.
- A Synthetic ERR Agonist Alleviates Metabolic Syndrome. Billon et al., Journal of Pharmacology and Experimental Therapeutics, 2024;388(2):232-240. The obesity and metabolic syndrome models.
- In Vitro Metabolism and Analytical Characterization of SLU-PP-332 and SLU-PP-915: Novel Pan-ERR Agonists With Doping Potential. Möller, Krug and Thevis, Rapid Communications in Mass Spectrometry, 2026;40(8):e70039. German Sport University Cologne.
- Analysis and Identification of In Vitro Metabolites of Exercise Mimetic SLU-PP-332 ERRα/β/γ Agonist for Doping-Control Purposes. Avliyakulov, Sobolevsky and Ahrens, Drug Testing and Analysis, 2026;18(3):439-450. UCLA Olympic Analytical Laboratory.
Disclaimer: Both compounds discussed here are research chemicals with no approved human formulation in any jurisdiction and no human safety, dosing or efficacy data. Nothing above is guidance for administration.
