ERR agonists and the "exercise mimetic" research question

SLU-PP-332 is a synthetic small-molecule agonist of the three estrogen-related receptors — ERRα, ERRβ, and ERRγ — and the compound most SLU-PP-332 research means when it says "exercise mimetic." The mechanism is well characterized and the rodent data are real, but every efficacy finding published to date came from mice or cells in culture. There has never been a published human clinical trial of SLU-PP-332 or of the related pan-ERR agonist SLU-PP-915. That absence is not a technicality — it is the most important fact about this compound.

What estrogen-related receptors regulate

The ERRs are nuclear receptors — transcription factors that bind DNA and switch gene programs on. They resemble the estrogen receptor structurally, hence the name, but do not bind estrogen, and no endogenous ligand has been established — which is what makes them orphan receptors. Two features made drugging them a non-obvious idea:

• They are constitutively active. Rather than sitting idle until a ligand arrives, ERRs are transcriptionally active by default; output depends less on ligand availability than on coactivator supply.
• Their principal coactivator is PGC-1α, which endurance exercise induces in skeletal muscle. Mootha and colleagues showed that ERRα, with GABPA/B, specifies the PGC-1α-dependent oxidative phosphorylation gene program, altered in diabetic human muscle (PMID: 15100410).

ERRα's downstream genes cover mitochondrial biogenesis, fatty acid oxidation, and oxidative fiber-type specification — the list endurance training produces — with expression highest in heart, slow-twitch muscle, kidney, and brown adipose.

Why a pan-ERR agonist was proposed as an exercise mimetic

"Exercise mimetic" is a term of art traceable to one paper. Narkar and colleagues reported in 2008 that a PPARδ agonist and exercise training synergistically increased oxidative myofibers and running endurance in mice, while the AMPK agonist AICAR increased running endurance in sedentary mice by 44% with no training at all (PMID: 18674809). That set the template — and the field's lasting ambiguity: one agent amplified training, the other partly substituted for it.

ERRs were a logical next target. Exercise raises PGC-1α; PGC-1α coactivates ERRα; ERRα drives the oxidative program. An agonist enters that cascade downstream of the coactivator, without requiring the muscle to contract. SLU-PP-332 was reported as exactly that — a pan agonist of all three ERRs, with highest potency at ERRα (PMID: 36988910).

What the research reported, and in which species

Findings are stated in the system where they were observed. No row describes an experiment in living humans.

Study	System studied	Reported finding
Billon 2023, ACS Chem Biol (PMID: 36988910)	Skeletal muscle cell line; mice	Increased mitochondrial function and cellular respiration in cells; increased type IIa oxidative fibers and running endurance in mice; ERRα-dependent
Hampton 2023, Eur J Med Chem (PMID: 37421886)	Synthetic chemistry; cell assays; mice	Identified SLU-PP-915 from a separate thiophene series; upregulated ERR target genes including Ddit4 and Pdk4
Wang 2023, Am J Pathol (PMID: 37717940)	21-month-old mice	Reversed age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines
Billon 2024, JPET (PMID: 37739806)	Diet-induced obese and ob/ob mice	Increased energy expenditure and fatty acid oxidation; decreased fat mass accumulation; improved insulin sensitivity
Xu 2024, Circulation (PMID: 37961903)	Mouse pressure-overload heart failure	Both compounds improved ejection fraction, reduced fibrosis and increased survival; ERRγ, not ERRα, was the main mediator
Bonanni 2025, Front Physiol (PMID: 40692696)	Myoblasts cultured from biopsies of inactive women	Downregulated NOX4 and upregulated SIRT1, PGC-1α and ERRα; promoted myotube formation in culture
Billon 2026, JPET (PMID: 41421047)	Mice, oral and intraperitoneal	SLU-PP-915 enhanced aerobic capacity orally; both compounds induced Ddit4 to levels matching or exceeding treadmill running, depending on the muscle

Two details in the final row get flattened elsewhere. The convergence claim is molecular: one exercise-responsive transcript reached comparable or higher induction in some muscles, which is not a claim that a compound reproduced training. And the same report described SLU-PP-915 as synergizing with training to further increase Ddit4 and mitochondrial gene expression. "Mimetic" implies replacement; that describes amplification.

Two compounds, not one

Secondary write-ups merge the two compounds, or cast the second as a reformulation of the first. They are separate molecules from separate chemical series: SLU-PP-915 was identified in 2023 from a thiophene series built on an acyl hydrazide template, carrying a boronic acid group that improved metabolic stability in microsomal assays (PMID: 37421886).

What separates them functionally is route. The 2026 characterization states plainly that SLU-PP-332 lacks oral bioavailability, and reports that SLU-PP-915 matched it on aerobic performance intraperitoneally and held comparable efficacy orally, adjusted for systemic exposure (PMID: 41421047). Metabolism differs too: a 2026 study identified nine metabolites for SLU-PP-332 — six Phase-I, three Phase-II conjugates — and seven, all Phase-I, for SLU-PP-915 (PMID: 41588687).

A separate 2026 study reported the first systematic structure-activity map of the SLU-PP-332 scaffold, finding analogues that matched the parent with improved ligand efficiency, solubility, or metabolic stability (PMID: 41850449). A field still publishing its foundational SAR roadmap is near the beginning of its work.

What counts as human data — and what does not

Searches return papers containing the word "human." Two categories exist; neither is a trial.

• Human tissue studied outside a body. The Frontiers in Physiology work cultured myoblasts from biopsies taken during hip arthroplasty in inactive women, then treated those cultures (PMID: 40692696). The cells were human; the administration was to a dish. The metabolite work used human liver S9 fraction and microsomes (PMID: 41588687) — human enzymes, not human subjects.
• Anti-doping method development. That study and a parallel one in Drug Testing and Analysis (PMID: 41688415) exist to build detection assays, and both frame these compounds as candidates for illicit performance-enhancing use. Laboratories build such assays in anticipation of misuse, not in response to approval — evidence of anticipated diversion, not of efficacy.

A 2026 systematic review of ERRα/β/γ activation surveyed the preclinical literature and concluded that clinical trials are needed to confirm efficacy and safety in humans (PMID: 42024694) — the field's own assessment of itself.

One further caution follows from the mechanism itself. ERRs are broadly expressed, and the rodent work reports activity in heart and kidney as readily as in muscle — the cardiac effects running mainly through ERRγ, not the ERRα that carries the endurance phenotype. A pan-agonist of a constitutively active receptor family acts well outside whichever tissue a model cares about, with long-term consequences uncharacterized in any species.

How this differs from MOTS-c and 5-amino-1MQ

These three are grouped under shared outcome vocabulary — metabolism, mitochondria, body composition — though they act at different layers of biology.

Compound	Molecular class	Direct target	Where the evidence sits
SLU-PP-332	Synthetic small molecule	Agonist at ERRα/β/γ — transcription factors	Rodent in vivo; human cells in vitro; no human trials
MOTS-c	Mitochondrial-derived peptide	Not a receptor agonist; AMPK-linked signaling	Mouse in vivo (PMID: 25738459); exercise-responsive (PMID: 33473109)
5-amino-1MQ	Small-molecule enzyme inhibitor	Inhibition of nicotinamide N-methyltransferase	Mouse in vivo (PMID: 29155147)

MOTS-c is the most instructive contrast: a mitochondrially encoded peptide that influenced metabolic homeostasis in mice (PMID: 25738459) and was later characterized as exercise-induced (PMID: 33473109) — an endogenous molecule exercise itself produces, not a synthetic ligand built for a receptor pocket; the MOTS-c research summary treats it on its own terms. 5-amino-1MQ inhibits an enzyme that methylates and consumes nicotinamide, placing it in the NAD⁺ economy rather than transcriptional control, as the 5-amino-1MQ research overview sets out. Interchangeability is not supported mechanistically.

What this means for research design

1. Label every carried-over finding with its species and system. The distance between "reported in mice," "reported in cultured human myoblasts," and "predicted from human liver microsomes" is the entire information content of this field. Secondary summaries collapse all three into "shown to."
2. Do not treat SLU-PP-332 and SLU-PP-915 as one compound. Separate scaffolds, separate identification papers, different oral bioavailability, different metabolite profiles. Findings do not transfer by default.
3. Identity confirmation matters more than usual. Active structure-activity programs generate families of close analogues, and the metabolite literature exists because these molecules are hard to tell apart. Identity should come from mass spectrometry and chromatography on the lot in hand, not from a label; every Merit lot ships with a certificate of analysis, and the certificate lookup resolves a lot number to its published document.

The honest summary of ERR agonism as of 2026: a clean mechanism, a coherent rationale, a reproducible rodent phenotype, active medicinal chemistry working through the parent compound's limitations — and no human evidence at all. All five are true at once, and an account that drops the fifth is not a shorter description of this field. It is a different one.

Notes

This is a research literature summary. It is not a recommendation for any research protocol, and it does not describe preparation or administration. For research use only. Not for human or veterinary use.

Selected references

1. Billon C, Appourchaux K, Côté I, Burris TP. An orally active estrogen receptor-related receptor agonist, SLU-PP-915, enhances aerobic exercise capacity. J Pharmacol Exp Ther 2026;393:103787. PMID: 41421047
2. Billon C, Sitaula S, Banerjee S, et al. Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity. ACS Chem Biol 2023;18:756–771. PMID: 36988910
3. Billon C, Schoepke E, Avdagic A, et al. A Synthetic ERR Agonist Alleviates Metabolic Syndrome. J Pharmacol Exp Ther 2024;388:232–240. PMID: 37739806
4. Hampton CS, Sitaula S, Billon C, et al. Development and pharmacological evaluation of a new chemical series of potent pan-ERR agonists, identification of SLU-PP-915. Eur J Med Chem 2023;258:115582. PMID: 37421886
5. Okda HE, Zhao P, Hayes M, et al. Chemical optimization of the exercise mimetic SLU-PP-332 enables insight into estrogen-related receptor signaling. Int J Biol Macromol 2026;355:151450. PMID: 41850449
6. Möller T, Krug O, Thevis M. In Vitro Metabolism and Analytical Characterization of SLU-PP-332 and SLU-PP-915: Novel Pan-ERR Agonists With Doping Potential. Rapid Commun Mass Spectrom 2026;40:e70039. PMID: 41588687
7. Avliyakulov NK, et al. Analysis and Identification of In Vitro Metabolites of Exercise Mimetic SLU-PP-332 ERRα/β/γ Agonist for Doping-Control Purposes. Drug Test Anal 2026;18:439–450. PMID: 41688415
8. de Souza-Lima J, Astrosa-Martin BD, Galaz-Rodríguez CA, et al. Pharmacological Activation of ERRα/β/γ as an Exercise Mimetic: Potential Therapeutic Applications. Rev Med Chil 2026;154:237–245. PMID: 42024694
9. Xu W, Billon C, Li H, et al. Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function. Circulation 2024;149:227–250. PMID: 37961903
10. Wang XX, Myakala K, Libby AE, et al. Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney. Am J Pathol 2023;193:1969–1987. PMID: 37717940
11. Bonanni R, Falvino A, Matticari A, et al. Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study. Front Physiol 2025;16:1616693. PMID: 40692696
12. Mootha VK, Handschin C, Arlow D, et al. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci USA 2004;101:6570–6575. PMID: 15100410
13. Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 2008;134:405–415. PMID: 18674809
14. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015;21:443–454. PMID: 25738459
15. Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 2021;12:470. PMID: 33473109
16. Neelakantan H, et al. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochem Pharmacol 2018;147:141–152. PMID: 29155147