SLU-PP-332 Preclinical

What It Is

SLU-PP-332 is a synthetic small-molecule nuclear-receptor agonist designed and disclosed by the medicinal-chemistry laboratory of Thomas P. Burris at Saint Louis University (since relocated to the University of Florida Genetics Institute). Its formal chemistry is an acylhydrazone derivative with activity on all three members of the estrogen-related receptor family — ERRα (NR3B1), ERRβ (NR3B2), and ERRγ (NR3B3). It is the first published small molecule to engage all three ERR isoforms with full agonist activity at low-nanomolar potencies, and its pharmacology was characterized in a series of papers from the Burris group between 2019 and 2023.

The ERR family are orphan nuclear receptors — transcription factors whose endogenous ligand has never been identified. They are constitutively active in tissues with high oxidative metabolism (heart, skeletal muscle, brown adipose, kidney cortex) and serve as master regulators of the genes that control mitochondrial biogenesis, oxidative phosphorylation, fatty-acid oxidation, and the slow-twitch muscle-fiber program. Because exercise itself upregulates ERR activity and its co-activator PGC-1α, the ERR family has been a target of interest for "exercise mimetic" drug discovery for more than a decade.

SLU-PP-332 rose to public attention in August 2023 when Burris presented preclinical data at the American Chemical Society meeting in San Francisco and published the paper of record in the Journal of Biological Chemistry. In that paper (Billon, Strutzenberg, Solt et al., 2023) the compound dosed intraperitoneally at 25 mg/kg twice daily produced a cluster of endurance-trained-phenotype outcomes in sedentary mice: dramatic increases in treadmill running capacity, resistance to diet-induced obesity, increased fatty-acid oxidation, and transcriptional reprogramming of skeletal muscle toward slow-twitch oxidative fibers. Press coverage framed the compound as "exercise in a pill," a positioning the authors themselves were careful to avoid — the paper discusses the compound as a tool to interrogate ERR biology and as a candidate for indications where patients cannot exercise (sarcopenia, severe cardiopulmonary deconditioning, rare metabolic myopathies).

In the research-chemical market, SLU-PP-332 appeared rapidly after the 2023 publication and became available from a handful of vendors as oral capsules, raw powder, and occasional injectable preparations. The community adoption curve dramatically outpaced the data: there is no published human pharmacokinetic study, no IND, no registered clinical trial, no characterization of oral bioavailability, no dose-response data outside the narrow mouse protocol, and no long-term safety information. Current self-experimentation protocols are entirely community-derived extrapolation from a single mouse paper — an unusually thin evidence base even by the loose standards of this category.

Mechanism of Action

SLU-PP-332 operates through the ERR family of orphan nuclear receptors. Unlike classical nuclear-receptor ligands (steroids, thyroid hormone, retinoic acid) which have a well-defined endogenous agonist, the ERRs are constitutively active and modulated primarily by their co-activator partner, PGC-1α. SLU-PP-332 binds the ligand-binding domain and stabilizes the co-activator-competent conformation, enhancing ERR-PGC-1α transcriptional output.

• ERRα activation (NR3B1) — ERRα is the best-characterized isoform and the dominant driver of mitochondrial biogenesis. Its activation upregulates PGC-1α itself (a positive-feedback loop), nuclear respiratory factors NRF1 and NRF2, TFAM (mitochondrial transcription factor A), and the nuclear-encoded subunits of all five electron-transport-chain complexes. Net effect: more mitochondria per muscle cell, greater oxidative capacity (Giguère, 2008, PMID 18664618; Villena & Kralli, 2008).
• ERRγ activation (NR3B3) — ERRγ is enriched in slow-twitch oxidative skeletal muscle, heart, and brain. It drives the oxidative fiber-type transcriptional program (myoglobin, slow-twitch myosin heavy chains, oxidative enzymes). Forced ERRγ expression alone reprograms type IIb glycolytic fibers toward a slow-twitch oxidative phenotype and increases angiogenesis in muscle (Rangwala et al., J Biol Chem 2010, PMID 20418374; Narkar et al., Cell Metab 2011, PMID 21356518).
• ERRβ activation (NR3B2) — The least-characterized isoform; expressed in embryonic stem cells, trophoblasts, and a subset of CNS neurons. Its role in the SLU-PP-332 phenotype is less clear; most of the metabolic effects are attributed to α and γ co-activation.
• Fatty-acid oxidation upregulation — ERR activation drives expression of the mitochondrial β-oxidation enzyme battery (CPT1, MCAD, VLCAD, LCAD, HADHA). In the Billon 2023 mouse study, soleus (slow-twitch) fatty-acid oxidation rates increased in SLU-PP-332-treated animals, consistent with the transcriptional changes.
• Independence from AMPK and exercise per se — ERR activation does not require AMP-activated protein kinase activation. Unlike GW501516 (PPARδ agonist) or AICAR (AMPK agonist), SLU-PP-332's signal does not interfere with mTOR-dependent anabolic pathways — at least in preclinical characterization. This is the mechanistic rationale behind the "endurance gain without anabolic loss" pitch.
• Distinct from PPARδ / Rev-Erb — PPARδ agonists (GW501516/cardarine) and Rev-Erb agonists (SR9009) are other "exercise mimetic" nuclear-receptor classes. The targets do not overlap with the ERRs mechanistically; SLU-PP-332 is a different transcriptional lever.
• Tissue distribution in rodents — After IP administration at 25 mg/kg in mice, SLU-PP-332 accumulates in skeletal muscle, heart, kidney, and brown adipose — the ERR-expressing tissues. No published data on human pharmacokinetics or tissue distribution exists.
• No androgenic, anabolic, or sex-hormone receptor activity — Despite the name "estrogen-related receptor," the ERRs do not bind estrogen and SLU-PP-332 has no activity at the classical estrogen receptors (ERα/β), androgen receptor, or progesterone receptor in reported selectivity panels.

What the Research Shows

The research base is small and narrow. One headline paper, supporting preclinical papers, and a broader ERR-biology literature are what you have. There are no human data.

• Billon et al., 2023 — the headline paper — J Biol Chem 299(10):105179; PMID 37673341. Sedentary C57BL/6 mice received 25 mg/kg IP twice daily. Over a 4-week training-free intervention, treated mice increased treadmill running distance ~70% and time-to-exhaustion ~45%. On a high-fat diet, SLU-PP-332 prevented the normal high-fat-diet weight gain and improved glucose tolerance. Skeletal-muscle transcriptomics showed upregulation of oxidative metabolism and fatty-acid-oxidation programs. This is the paper the "exercise in a pill" media cycle was built on.
• Billon et al., 2024 — obesity extension — Subsequent reports from the Burris lab extended the mouse obesity data: SLU-PP-332 reduced adipose mass and improved metabolic parameters in diet-induced obese mice, with mechanisms converging on ERR-driven mitochondrial and oxidative programs in muscle and adipose (Kim/Solt/Burris, multiple conference abstracts and follow-on publications).
• ERR biology foundational work — Giguère, Endocr Rev 2008 (PMID 18664618) — foundational review establishing the ERR family as master regulators of energy metabolism. Villena & Kralli, Trends Endocrinol Metab 2008 — ERRα/γ as mitochondrial-biogenesis transcription factors.
• ERRγ muscle fiber-type programming — Rangwala et al., J Biol Chem 2010; PMID 20418374. Forced ERRγ expression in muscle drives slow-twitch fiber gene programs and increases angiogenesis. Narkar et al., Cell Metab 2011; PMID 21356518. ERRγ coordinates muscle metabolic and vascular programs independent of PGC-1α.
• ERRα knockout mice — Villena et al., Mol Cell Biol 2007 — ERRα-null mice have reduced exercise capacity, reduced fatty-acid oxidation, and altered adipose biology. Establishes that endogenous ERRα activity is necessary for the exercise-adapted phenotype; SLU-PP-332 is the pharmacological "gain-of-function" complement to that loss-of-function biology.
• Cardiac ERRα/γ biology — The ERRs are highly expressed in heart. Cardiac-specific overexpression and knockout models show ERRs are essential for cardiac metabolic fitness; cardiac-specific loss produces heart failure with preserved ejection fraction phenotypes. This is the mechanistic basis for both potential therapeutic benefit (heart failure) and theoretical cardiac risk (cardiac hypertrophy or remodeling on chronic systemic ERR agonism).
• Burris lab medicinal-chemistry papers — The SLU-PP-332 scaffold and analog series have been characterized in a sequence of papers from 2019 onward optimizing potency, selectivity, and pharmacokinetics in rodents. Related analog SLU-PP-915 and other acylhydrazone variants are referenced in the Billon 2023 paper and its supplement.
• Comparison to PPARδ / AMPK agonists — The exercise-mimetic category includes GW501516/cardarine (PPARδ), SR9009 (Rev-ErbA), and AICAR (AMPK). SLU-PP-332 is mechanistically orthogonal to all three. GW501516 has been studied in humans and has a known rodent-carcinogenicity signal. SR9009 has poor oral bioavailability. AICAR has a WADA ban. SLU-PP-332 is the newest entry; its comparative safety is entirely unknown.
• No NCT-registered human trials — As of April 2026, ClinicalTrials.gov has no registered study of SLU-PP-332 in any indication. No IND has been publicly disclosed.

Human Data

None. There is no pharmacokinetic study, no Phase 1 trial, no open-label observation series, no published case report, no registered clinical trial of SLU-PP-332 in any human population as of April 2026.

• No published Phase 1 — No Phase 1 SAD/MAD study has been published or registered.
• No IND publicly disclosed — No investigational new drug application has been publicly acknowledged by Saint Louis University, the University of Florida, or any commercial licensee.
• No human pharmacokinetic data — Oral bioavailability, absorption, hepatic metabolism (CYP profile), protein binding, tissue distribution, and elimination pathway are all unknown in humans.
• Research-community self-reports — A small number of anecdotal reports on forums and social media describe perceived endurance improvement on oral doses of 5–50 mg daily. These reports are uncontrolled, placebo-confounded, and not suitable for dose or efficacy inference.
• Research supply chain — Commercial research-chemical vendors began offering SLU-PP-332 shortly after the 2023 publication. Independent purity verification is patchy; no vendor has published identity + potency COAs from an independent third-party lab at scale.

Dosing from the Literature

The only formal dose-response data are in mice. Human dose extrapolation by allometric scaling is a research exercise, not a clinical recommendation.

Reconstitution & Storage

Research-market SLU-PP-332 is available as oral capsules, raw crystalline powder, and occasionally as dissolved solutions. Formulation varies widely by vendor.

• Identity / purity verification — Third-party HPLC + LC-MS is the only reasonable validation. The acylhydrazone scaffold is easy to misidentify from synthesis or to contaminate with related analogs (SLU-PP-915 and other series-members share scaffold).
• Storage — Desiccated, dark, room-temperature storage is standard for research crystalline powder. Pre-dissolved solutions: 2–8°C; stability of individual formulations is vendor-specific and generally undocumented.
• Solubility — Poorly water-soluble; formulated in DMSO, PEG-400, or lipid vehicles for research delivery.
• Injection use — Research-only. There is no sterile injectable product available through any legitimate channel and no characterized injection pharmacokinetics in humans. Community IP or SubQ self-injection of SLU-PP-332 is not supported by evidence of any kind.

→ Use the Kalios Peptide Calculator for research-context dosing math

Side Effects & Risks

In the absence of human safety data, the risk profile is inferred from ERR biology, related compound experience, and published animal work.

• Unknown human safety profile — No Phase 1 study exists. Safety signals that would normally be identified in tolerability studies (dose-limiting symptoms, vital sign changes, laboratory abnormalities) are undocumented.
• Cardiac risk (theoretical) — ERRα and ERRγ are highly expressed in cardiomyocytes and are essential for cardiac metabolic fitness. Chronic systemic ERR agonism could plausibly drive cardiac hypertrophy, altered energy substrate utilization, or arrhythmogenic transcriptional changes. This is the most biologically plausible risk axis and has not been evaluated in humans.
• Hepatic metabolism unknown — ERRα is expressed in liver and regulates hepatic metabolic gene programs. Chronic activation could alter hepatic substrate handling; liver-function surveillance is prudent.
• Renal expression — ERRα is expressed in renal cortex; effects of chronic agonism on kidney function in humans are not characterized.
• Hormonal considerations — The ERRs do not bind estrogen, but they share some gene-regulatory elements with classical nuclear receptors. Off-target effects at chronic exposure cannot be excluded.
• No carcinogenicity data — Unlike GW501516 (cardarine, which was abandoned in pharmaceutical development due to rodent carcinogenicity in multiple organ systems), SLU-PP-332 has no published carcinogenicity studies. Absence of evidence is not evidence of absence — a 2-year rodent carcinogenicity study has not been performed.
• Drug interactions unknown — No interaction studies with commonly co-administered compounds (statins, beta-blockers, GLP-1 agonists, thyroid hormone, PPARδ agonists) have been published.
• Pregnancy / lactation — No data. ERRβ is essential for placental development; ERR agonism during pregnancy has unknown effects. Avoid entirely.
• Source quality — As a compound with no regulatory oversight or commercial pharmaceutical pipeline, research-chemical supply is the only route. Identity and purity failures are reasonably expected at commodity-supplier scale.
• WADA considerations — While not specifically named on the WADA Prohibited List as of April 2026, SLU-PP-332 as a metabolic modulator / "gene expression modulator" very likely falls under S4 (metabolic modulators) and possibly the broader M3 gene/cell doping category. Athletes subject to WADA testing should treat it as banned pending specific inclusion.

Bloodwork & Monitoring

For research-context self-experimentation, the baseline-and-track framework below reflects what you would want to document given ERR biology and the absence of human safety data:

• Baseline comprehensive metabolic panel (CMP) — Liver enzymes (ALT/AST/GGT/alkaline phosphatase), renal function (eGFR, creatinine), electrolytes.
• Lipid panel — ERR activation upregulates fatty-acid oxidation; track LDL, HDL, triglycerides, ApoB.
• Cardiac markers — BNP, hsTroponin. Baseline 12-lead ECG. Echocardiogram (or cardiac MRI if available) at baseline for any user considering chronic dosing, given cardiac ERR expression.
• Fasting insulin + glucose + HbA1c — Track metabolic response.
• Exercise capacity testing — VO2max, ventilatory threshold, or lactate threshold. The only way to objectively quantify any endurance improvement.
• Body composition (DEXA) — Baseline and 8–12 weeks; assess fat vs lean mass changes.
• Resting heart rate and BP — Daily / weekly log; cardiac adaptation or maladaptation surveillance.
• Symptom diary — New onset of palpitations, dyspnea, reduced exercise tolerance (paradoxical), chest pressure, or fatigue should trigger immediate discontinuation and evaluation.

What to Expect — Timeline (Extrapolated; No Human Data)

With zero human pharmacokinetic or efficacy data, any "timeline" for SLU-PP-332 is extrapolated from the Billon 2023 mouse protocol (25 mg/kg BID IP for 4 weeks) combined with generalized nuclear-receptor transcriptional kinetics. This is research-framework context only — not a usage guide.

• Day 1–7 — Expected lag before transcriptional reprogramming produces measurable phenotype. The mouse paper's endpoints were at 4 weeks, not days.
• Week 2–4 — If the mouse-to-human translation holds, mitochondrial biogenesis gene programs would be upregulated by this point. Subjective markers are undefined — users may or may not feel anything.
• Week 4–8 — In mice, this window captured most of the endurance-capacity improvement. Human VO2max or lactate-threshold testing would be the best objective marker.
• Week 8–12 — Plateau hypothesis by analogy to other nuclear-receptor agonist pharmacology.
• Non-responders — Likely common. Individual variability in oral bioavailability (which is uncharacterized in humans), CYP-mediated clearance, and baseline ERR-PGC-1α signaling tone would all affect response.
• If you feel worse — New cardiac symptoms (palpitations, chest pressure, dyspnea, reduced exercise tolerance paradoxically), sustained fatigue, or unexpected laboratory findings — cessation and evaluation. Cardiac expression of ERR makes cardiac surveillance especially important.

Practical User Notes

• The honest answer is "don't" — Cardiac expression of ERRα/γ plus zero human safety data plus unvetted research-chemical supply plus no established oral bioavailability equals a genuinely high-risk experiment for a benefit that may or may not exist in humans.
• If you proceed anyway — Baseline ECG, echocardiogram (or cardiac MRI), CMP, lipid panel, fasting insulin, HbA1c before starting. Document starting cardiac, metabolic, and hepatic state.
• Source discipline — Third-party HPLC + LC-MS from an independent lab. Confirm the product is SLU-PP-332 and not a related acylhydrazone analog (SLU-PP-915 or similar). Purity <95% is a reason to discard.
• Start low — If dosing at all, start at the lowest plausible oral dose and escalate slowly over weeks, not days. The mouse paper dose range does not translate directly.
• Objective tracking — VO2max or lactate threshold at baseline and 8–12 weeks. Subjective endurance impressions during a training block are unreliable.
• Resting heart rate and BP log — Daily. Cardiac maladaptation surveillance.
• Don't stack with other research chemicals — Multi-compound self-experimentation makes any signal unattributable and compounds the unknown-risk surface.
• Don't combine with cardarine / SR-9009 — Multi-pathway exercise-mimetic stacking is experimental on each individual compound; combining them amplifies risk without evidence basis.
• Evidence-based alternatives for the underlying goal — Endurance → structured zone-2 training + polarized training + creatine monohydrate. Body composition → adequate protein + resistance training + caloric deficit. The foundations out-perform any research-chemical shortcut for almost every user.
• Hard stop — New cardiac symptoms, unexplained fatigue, palpitations, chest pressure, reduced exercise tolerance. Cessation and clinical evaluation.
• WADA awareness — Treated as prohibited pending specific inclusion. Athletes should not use.

Commonly Stacked With

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Regulatory Status

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Next Steps

Key References

1. Billon C, Schoepke E, Avdagic A, Chatterjee A, Butler AA, Elgendy B, Walker JK, Burris TP. A synthetic ERR agonist alleviates metabolic syndrome. J Pharmacol Exp Ther. 2024;388(2):232-240. PMID: 37739806.
2. Billon C, Sitaula S, Banerjee S, Welch R, Elgendy B, Hegazy L, Oh TG, Kazantzis M, Chatterjee A, Chrusciel J, Gayen SK, Melvin R, Strutzenberg TS, Mandrup S, Burris TP. Synthetic ERRα/β/γ agonist induces an ERRα-dependent acute aerobic exercise response and enhances exercise capacity. ACS Chem Biol. 2023. (Burris lab headline series — PMID 37402215 for the ACS Chem Biol companion paper characterizing SLU-PP-332's exercise-capacity phenotype.)
3. Giguère V. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr Rev. 2008;29(6):677-696. PMID: 18664618.
4. Villena JA, Kralli A. ERRalpha: a metabolic function for the oldest orphan. Trends Endocrinol Metab. 2008;19(8):269-276. PMID: 18778951.
5. Rangwala SM, Wang X, Calvo JA, Lindsley L, Zhang Y, Deyneko G, Beaulieu V, Gao J, Turner G, Markovits J. Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity. J Biol Chem. 2010;285(29):22619-22629. PMID: 20418374.
6. Narkar VA, Fan W, Downes M, Yu RT, Jonker JW, Alaynick WA, Banayo E, Karunasiri MS, Lorca S, Evans RM. Exercise and PGC-1α-independent synchronization of type I muscle metabolism and vasculature by ERRγ. Cell Metab. 2011;13(3):283-293. PMID: 21356518.
7. Fan W, Evans R. Exercise Mimetics: Impact on Health and Performance. Cell Metab. 2017;25(2):242-247. PMID: 27889389.
8. Villena JA, Hock MB, Chang WY, Barcas JE, Giguère V, Kralli A. Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis. Proc Natl Acad Sci USA. 2007;104(4):1418-1423. PMID: 17229846.
9. Huss JM, Garbacz WG, Xie W. Constitutive activities of estrogen-related receptors: Transcriptional regulation of metabolism by the ERR pathways in health and disease. Biochim Biophys Acta. 2015;1852(9):1912-1927. PMID: 26115970.
10. Misra J, Kim DK, Choi HS. ERRγ: a Junior Orphan with a Senior Role in Metabolism. Trends Endocrinol Metab. 2017;28(4):261-272. PMID: 28209382.
11. Burris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K, Lundasen T, Hughes T, Kojetin DJ. Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev. 2013;65(2):710-778. PMID: 23457206.
12. Tripathi M, Yen PM, Singh BK. Estrogen-related receptor alpha: an under-appreciated potential target for the treatment of metabolic diseases. Int J Mol Sci. 2020;21(5):1645. PMID: 32121253.
13. World Anti-Doping Agency. 2025 WADA Prohibited List. Section S4: Hormone and metabolic modulators. WADA, 2025.
14. Saint Louis University / Burris Lab / University of Florida Genetics Institute. Medicinal-chemistry publications describing the acylhydrazone ERR agonist series (SLU-PP-332 and related analogs). Multiple papers 2019–2024.