SLU-PP-332 (oral)

SLU-PP-332 is a synthetic small molecule (C18H14N2O2, 290.32 g/mol) developed at Saint Louis University in the early 2000s. It is a pan-agonist of the oestrogen-related receptors ERRα, ERRβ and ERRγ, orphan nuclear receptors acting downstream of PGC-1α, with greatest potency at ERRα. The ERRs share structural homology with oestrogen receptors but do not bind oestrogen, and agonism has no effect on circulating oestrogen. The axis governs mitochondrial biogenesis, oxidative phosphorylation gene expression and fatty-acid oxidation — hence the "exercise mimetic" label: the transcriptional signature of endurance adaptation without the mechanical stimulus.

This is the oral route, supplied as 300 mcg and 1,000 mcg capsules, with commercial products spanning roughly 100 mcg to a few milligrams per capsule. Note the scale difference against the injectable page on this site, which runs 1.25–2.5 mg subcutaneously; the routes are dosed on entirely different scales and are not interchangeable.

Regulatory and evidence status: not FDA approved, never tested in humans in vivo, classified as a research chemical only, and WADA-prohibited under S0 (unapproved substances) and the metabolic modulator/exercise mimetic categories. Avliyakulov, Sobolevsky and Ahrens (2026) characterised 22 in vitro metabolites in human liver microsomes for doping-control detection. All in vivo efficacy data are murine; the only human tissue data are the in vitro muscle-cell pilot of Bonanni et al. (2025).

Physicochemically the compound is hydrophobic: insoluble in water, sparingly soluble in DMSO (58 mg/mL) and slightly soluble in ethanol (2 mg/mL). Every published study delivered it intraperitoneally in a DMSO-based vehicle; no oral formulation has been published, and the developers have stated the structure needs modification for oral delivery. That fact dominates everything about this route.

The earlier gating rule is retained: 1,000 mcg capsules are restricted to second-or-later cycles in users who tolerated lower doses.

ERRα is the dominant transcriptional regulator of oxidative metabolism in skeletal muscle. Acting with PGC-1α as co-activator, it drives the gene programmes for mitochondrial biogenesis, β-oxidation and electron-transport-chain efficiency. Endurance training raises ERRα activity as part of the normal adaptive response, producing more mitochondria, a shift toward lipid substrate use and improved endurance.

SLU-PP-332 agonises ERRα (and ERRβ/γ) directly, reproducing that transcriptional response without contractile stimulus. Billon et al. (2023) confirmed mechanism by repeating the exercise-capacity experiment in muscle-specific ERRα knockout mice, in which the effects were abolished, excluding off-target explanations. In the heart-failure model of Xu et al. (2024), ERRγ rather than ERRα was identified as the principal mediator of cardioprotection, with upregulation of cardiac fatty-acid-metabolism and mitochondrial genes preventing metabolic failure in the pressure-overloaded myocardium.

The limitation is scope. Exercise engages AMPK, mTOR, BDNF, IGF-1, myokine release, bone remodelling and immune signalling among many others; SLU-PP-332 engages one nuclear-receptor axis. It is a partial mimetic of a single limb of the adaptation.

Pharmacokinetics are rodent-only and thin. At 30 mg/kg IP, plasma exposure was 0.2 micromolar and muscle exposure 0.6 micromolar at 6 hours post-injection. Estimated plasma elimination half-life is approximately 8 to 10 hours, though no formal pharmacokinetic study establishing this has been published. Blood-brain-barrier penetration is poor.

For the oral route specifically, the mechanistic story stops at the gut wall. The compound is water-insoluble and must dissolve to cross the roughly 100 micrometre aqueous layer of the intestinal mucosa. Absorption from a dry-powder capsule therefore depends on bile secretion, co-ingested fat and individual gut variability; no oral bioavailability study exists, and claims of 40 to 50% oral bioavailability circulating online have no supporting data.

No human pharmacodynamic data exist. In murine models, ERR agonism produced the following: a 70% increase in running time and 45% increase in distance with more type IIa oxidative fibres, higher mitochondrial DNA content and increased grip strength after 6 and 13 days (Billon et al., 2023); approximately 12% body-weight loss over 28 days in diet-induced obese mice with minimal fat-mass gain, increased energy expenditure and fatty-acid oxidation, improved glucose tolerance and insulin sensitivity, reduced hepatic steatosis, and no change in food intake or activity (Billon et al., 2024); reversal of age-related albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines in 21-month-old mice over 8 weeks, described as mimicking caloric restriction (Wang et al., 2023); and improved ejection fraction, reduced fibrosis and increased survival in pressure-overload heart failure (Xu et al., 2024). In vitro, human myocytes from inactive elderly women showed reduced oxidative stress, enhanced SIRT1 and PGC-1α, improved survival, myotube fusion and lower senescence markers (Bonanni et al., 2025).

Lipid effects: plasma total cholesterol, HDL and triglycerides all decreased; LDL was unchanged. The HDL reduction is the one adverse signal from the mouse literature.

Translating any of this to oral capsules is speculative. All efficacy data used intraperitoneal delivery in a DMSO/PEG 300/Tween 80 vehicle. Oral bioavailability is unmeasured and, given water insolubility, likely far lower and highly variable. The pattern in user reports — responders cluster among those dosing with fats, sublingually or at higher doses; non-responders overwhelmingly among standard capsule users — is consistent with an absorption-limited effect rather than a pharmacological null.

The earlier operating instructions (morning, fasted, daily or 5-on/2-off, no desensitisation expected over a short cycle) are retained for reference. The fasted requirement conflicts with the observation that co-ingested fat probably improves solubilisation of a lipophilic compound; neither position is backed by an oral study.

No human clinical data exist, so no evidence-based expectation of onset, magnitude or duration can be given. What follows is aggregated user report and carries correspondingly low weight.

Reported positives: increased energy, elevated heart rate and perceived metabolic demand during training (subjectively, feeling more out of breath), improved cardio endurance, improved recovery and focus, and gradual fat loss over 4 to 8 weeks when combined with diet and training. One user reported 11 pounds lost over 4 weeks with improved vascularity while stacking with other compounds. Sublingual administration is reported by some to produce more consistent effects than swallowed capsules.

Reported negatives: a large proportion of users report no effect at any dose. Titration from 250 mcg to 1500 mcg daily without perceptible change, 8 capsules taken at once without effect, and over a month at 1000 mcg daily without measurable results are all reported.

The distribution is not random. Responders cluster among those dosing with fats, dosing sublingually, or using higher doses; non-responders cluster among standard oral capsule users. This is exactly the pattern an absorption-limited, water-insoluble compound would produce: inter- and intra-individual variability in dissolution across the intestinal aqueous layer, dependent on bile output and co-ingested lipid.

Anecdotal adverse effects: hypoglycaemia at higher doses, sleep disturbance, mild gastrointestinal discomfort and fatigue, all sparse and unverified. Hypoglycaemia is mechanistically plausible given increased metabolic rate and fatty-acid oxidation, particularly under fasting, caloric restriction or concurrent glucose-lowering agents — relevant given the earlier fasted-morning instruction.

No multi-month or multi-year safety data exist in any species; the longest study was 8 weeks. Whatever is or is not felt over a 4 to 8 week cycle says nothing about long-term risk, including the unresolved question of chronic ERRα agonism in tissue that harbours undetected malignancy.

No human dosing protocol exists. No clinical trial has administered SLU-PP-332 to humans by any route, no study has tested oral administration in any species, and no oral bioavailability study has been published. No dose is proposed here.

Preclinical exposure, all intraperitoneal in a DMSO-based vehicle: 50 mg/kg twice daily for 7 to 15 days (Billon et al., 2023); 50 mg/kg twice daily for 28 days (Billon et al., 2024); 25 mg/kg daily for 8 weeks (Wang et al., 2023); 25 mg/kg twice daily, duration unspecified (Xu et al., 2024). Allometric conversion (divide by 12.3, standard FDA guidance) yields approximately 140 mg/day for 25 mg/kg and approximately 560 mg/day for 50 mg/kg twice daily in a 154 lb adult, assuming 100% bioavailability from IP delivery. Commercial capsules contain 100 mcg to a few milligrams. The gap between research exposure and marketed content is two to three orders of magnitude before the absorption question is even reached.

The absorption question is severe. SLU-PP-332 is insoluble in water, sparingly soluble in DMSO (58 mg/mL) and slightly soluble in ethanol (2 mg/mL). Dissolution across the roughly 100 micrometre intestinal aqueous layer from dry powder is unpredictable and depends on bile secretion, co-ingested fat and individual gut variability. Co-ingestion with fats probably improves solubilisation of a lipophilic compound but has not been tested. Online claims of 40 to 50% oral bioavailability have no supporting study. The developers have stated in their papers that the structure requires modification for oral delivery.

Earlier instructions, retained for reference and not endorsed: 4–8 week cycle, 2–4 week washout; daily dosing (short cycle, desensitisation not expected) or 5-on/2-off; morning, fasted. 300 mcg capsules: 300 mcg daily in week 1, then 300–600 mcg once daily for the remainder. 1,000 mcg capsules: 1,000 mcg each morning for the cycle, gated to second-or-later cycles with documented tolerance at lower doses. Note the fasted instruction conflicts with the solubilisation argument for fat co-ingestion, and that anecdotal hypoglycaemia at higher doses argues against fasted dosing.

Reconstituting capsule contents or raw powder in bacteriostatic water for injection does not produce a solution; it produces a particulate suspension. The published vehicle is 5% DMSO, 40% PEG 300, 5% Tween 80 and 50% sterile water. That is the injectable route's problem and is covered on the injectable page; it is not a workaround for the oral one.

Five direct efficacy studies plus one analytical study; all efficacy data are murine or in vitro. No human in vivo data exist.

Billon, Sitaula, Banerjee et al., ACS Chemical Biology, 2023. Male C57BL/6J mice, 50 mg/kg IP twice daily for 7–15 days: running time +70%, distance +45%, increased type IIa oxidative fibres and mtDNA content, grip strength up at 6 and 13 days. Muscle-specific ERRα knockouts showed no response (25 mg/kg for 15 days also tested in the knockout model), establishing ERRα dependence.

Billon, Schoepke, Avdagic et al., JPET, 2024. HFD-obese mice, 50 mg/kg IP twice daily for 28 days: ~12% body-weight loss, minimal fat-mass gain, increased energy expenditure and fatty-acid oxidation, improved insulin sensitivity, no change in food intake or activity. Total cholesterol, HDL and triglycerides decreased; LDL unchanged.

Wang, Myakala, Libby et al., American Journal of Pathology, 2023. 21-month-old mice, 25 mg/kg IP daily for 8 weeks: reversal of albuminuria, podocyte loss and mitochondrial dysfunction; reductions in TGF-β, PAI-1, Col IV, macrophage and tubular injury markers. Human kidney tissue showed parallel age-related ERR pathway decline.

Xu, Billon, Li et al., Circulation, 2024. Pressure-overload heart failure, 25 mg/kg IP twice daily: improved ejection fraction, reduced fibrosis, increased survival. ERRγ, not ERRα, was the principal mediator of cardioprotection via enhanced cardiac fatty-acid metabolism.

Bonanni, Falvino, Matticari et al., Frontiers in Physiology, 2025. Muscle from 20 women at hip replacement (active n=10, inactive n=10); in vitro treatment of inactive-donor myocytes reduced oxidative stress, raised SIRT1 and PGC-1α, promoted survival and fusion, reduced senescence markers.

Avliyakulov, Sobolevsky, Ahrens, Drug Testing and Analysis, 2026. 22 metabolites identified in human liver microsomes for doping control.

Pharmacokinetics: at 30 mg/kg IP, plasma 0.2 µM and muscle 0.6 µM at 6 hours; estimated rodent plasma half-life ~8–10 hours without a formal PK study; poor blood-brain barrier penetration.

Route-critical caveats: every study used IP injection in a DMSO-based vehicle. No oral administration study and no oral bioavailability study exist; the developers state the structure needs modification for oral delivery. The compound is water-insoluble (58 mg/mL in DMSO, 2 mg/mL in ethanol). Allometric conversion (÷12.3) of the mouse doses gives ~140–560 mg/day for a 154 lb adult, assuming 100% bioavailability — orders of magnitude above the 100 mcg to few-milligram capsule contents on the market.