SLU-PP-332

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$79.99

60 capsules · capsule

SLU-PP-332 acts through pan-agonism of the three estrogen-related receptors (ERRα/NR3B1, ERRβ/NR3B2, ERRγ/NR3B3), a subfamily of orphan nuclear receptors that regulate oxidative metabolism, mitochondrial biogenesis, and exercise-responsive gene expression. The ERRs are constitutively active transcription factors without well-characterized endogenous ligands, so pharmacologic "activation" means improving coactivator recruitment and transcriptional output rather than turning on a receptor that was otherwise off. SLU-PP-332 binds the ligand-binding domain of all three ERR isoforms and stabilizes receptor conformations that preferentially recruit coactivators including PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), the master regulator of mitochondrial biogenesis and oxidative metabolism. The downstream transcriptional response produces a coordinated program of mitochondrial biogenesis, fatty acid oxidation enzyme expression, oxidative phosphorylation complex synthesis, and slow-twitch muscle fiber marker upregulation — the gene expression signature of endurance exercise. The specific genes induced by ERR/PGC-1α complex activation include mitochondrial biogenesis factors (NRF1, NRF2, TFAM for mitochondrial DNA replication and maintenance), fatty acid oxidation enzymes (CPT1A and CPT1B for fatty acid transport into mitochondria, ACADM and ACADL and ACADVL for fatty acyl-CoA dehydrogenation, HADHA and HADHB for fatty acyl-CoA β-oxidation), TCA cycle enzymes, components of all four electron transport chain complexes, ATP synthase subunits, mitochondrial fusion and fission machinery (MFN1, MFN2, OPA1, DRP1), and slow-twitch myosin heavy chain (MYH7) and troponin isoforms. The coordinated upregulation of this gene program shifts cellular metabolism toward oxidative phosphorylation from carbohydrate-dominated glycolysis, increases mitochondrial content and function, and produces a muscle phenotype resembling that of endurance-trained tissue. The pan-agonist profile — hitting ERRα, ERRβ, and ERRγ simultaneously — distinguishes SLU-PP-332 from selective isoform-specific ligands. Each ERR isoform has tissue-enriched expression: ERRα is broadly expressed with highest levels in metabolically active tissues (skeletal muscle, heart, brown adipose tissue, liver, kidney); ERRβ is most prominent in undifferentiated cells and specific neural populations; ERRγ is most enriched in heart, slow-twitch muscle, and brown adipose tissue. Pan-activation captures the full tissue-distributed metabolic program rather than a restricted subset. Published rodent studies with SLU-PP-332 demonstrated functional consequences consistent with this mechanism: increased treadmill running endurance in mice without prior training, elevated expression of oxidative metabolism genes in skeletal muscle at both mRNA and protein levels, increased mitochondrial content measured by electron microscopy and respirometry, elevated fatty acid oxidation rates in isolated muscle and heart tissue, and improved whole-body oxygen consumption during activity. In diet-induced obesity models, SLU-PP-332 produced reductions in fat mass and improvements in metabolic parameters. In pressure-overload cardiac hypertrophy and heart failure models, SLU-PP-332 preserved or improved cardiac function, reduced pathological remodeling, and improved exercise tolerance. The cardiac effects specifically reflect the dependence of the heart on fatty acid oxidation and the critical role of ERRα/γ in cardiac energetics. Beyond the core transcriptional mechanism, SLU-PP-332 produces secondary effects through interactions with other nuclear receptor pathways and metabolic signaling networks. The coactivator PGC-1α is a shared coactivator for multiple nuclear receptors including PPARs, thyroid hormone receptor, and glucocorticoid receptor, and pharmacologic recruitment of PGC-1α by ERR agonism affects the overall balance of nuclear receptor signaling. AMPK signaling is also relevant because AMPK directly phosphorylates and activates PGC-1α, and the interplay between SLU-PP-332's pharmacologic activation of PGC-1α-dependent transcription and endogenous AMPK signaling during exercise or fasting creates a context where effects can be additive or saturating depending on baseline state. The mechanism has important limitations that should be understood. First, driving tissues toward oxidative metabolism pharmacologically produces a transcriptional signature similar to exercise but does not reproduce the mechanical loading, cardiovascular conditioning, or neuroendocrine effects of actual exercise. SLU-PP-332 is a transcriptional exercise mimetic, not an actual exercise replacement. Second, sustained pharmacologic ERR activation may produce adaptive regulatory changes that attenuate the effect over time through homeostatic mechanisms — receptor downregulation, coactivator redistribution, or compensatory changes in metabolic sensors. The timescale and magnitude of such adaptation in humans is unknown. Third, the effects of chronic ERR activation on tissues where fibrotic fibrosis or remodeling could be adverse (cardiac ventricle under chronic load, renal tissue with glomerular disease) are not comprehensively characterized, and pharmacologic ERR agonism could have tissue-specific effects that differ from the net-positive rodent picture. Fourth, the specific pharmacological limitations of SLU-PP-332 — poor oral bioavailability, rapid clearance, need for IP administration in rodent studies — restrict both its clinical development potential and its practical use by self-experimenters. These limitations are specifically addressed by the second-generation compound SLU-PP-915, which is why most users interested in this drug class have migrated to the newer compound. Users considering SLU-PP-332 specifically should understand they are working with the first-generation molecule with known PK limitations.

SLU-PP-332 is the first-generation synthetic pan-agonist of the estrogen-related receptors (ERRα, ERRβ, ERRγ) developed by the laboratory of Thomas Burris at Saint Louis University and reported in a landmark 2023 publication that established ERR pan-agonism as a pharmacologically tractable exercise-mimetic drug mechanism. The compound is the chemical scaffold from which the second-generation, orally bioavailable successor SLU-PP-915 was developed, and the SLU-PP-332 story is essential context for understanding the ERR agonist field because SLU-PP-332's original rodent pharmacology is what generated the initial enthusiasm for this drug class and its limitations (specifically its poor oral bioavailability) are what motivated the second-generation development program. The original publication from the Burris group established that SLU-PP-332 administration to mice produces a transcriptional, functional, and physiological signature that overlaps substantially with the effects of endurance exercise — enhanced running endurance on treadmill testing, increased mitochondrial biogenesis in skeletal muscle, shifts in muscle fiber type toward slow-twitch oxidative phenotype, elevated fatty acid oxidation, favorable body composition changes in diet-induced obesity models, and cardiac functional improvements in pressure-overload heart failure models. These effects are mediated through coordinated activation of the three ERR isoforms (ERRα, ERRβ, ERRγ), nuclear receptor transcription factors that sit at the top of the regulatory cascade controlling oxidative metabolism, and through recruitment of PGC-1α and other transcriptional coactivators that together drive expression of the exercise-responsive gene program. SLU-PP-332 specifically attracted intense scientific and popular media attention in 2023-2024 because the rodent data was presented in accessible terms — "a drug that mimics the effects of exercise" — and the social and medical appeal of such a compound for patients who cannot exercise due to frailty, cardiac disease, orthopedic limitations, or other constraints is obvious. The public discussion outran the evidence in typical fashion: the rodent data is real and consistent, but human validation of the exercise-mimetic premise requires clinical trials that have not been conducted for SLU-PP-332 or any related compound. SLU-PP-332's major pharmacological limitation, documented in the published work, is poor oral bioavailability. Every published rodent study with SLU-PP-332 used intraperitoneal (IP) injection as the route of administration, not oral dosing. IP administration in mice is routine in preclinical research but is obviously not a viable route for human chronic therapy, and this limitation was the specific motivation for the Burris group to develop the second-generation compound SLU-PP-915 with improved oral PK. The practical reality in April 2026 is that SLU-PP-332 remains a first-generation research chemical that has been largely superseded by SLU-PP-915 for self-experimentation purposes where oral dosing is preferred, though SLU-PP-332 continues to be sold by research-chemical vendors and used by a subset of biohackers who prefer the first-generation compound either for cost reasons, availability reasons, or preference for the more extensively characterized parent molecule. No human clinical trials of SLU-PP-332 have been registered or published, no IND applications for it have been publicly disclosed, and no pharmaceutical-grade supply exists. This entry covers the detailed mechanism of ERR pan-agonism as established in the original SLU-PP-332 work, the specific preclinical pharmacology including cardiovascular, metabolic, and musculoskeletal endpoints, the context provided by the broader ERR biology literature, the theoretical and practical concerns with self-administration of an unvalidated nuclear receptor agonist, how SLU-PP-332 differs practically from SLU-PP-915 for self-experimenters, and how SLU-PP-332 fits into the stacking landscape alongside other metabolic and exercise-mimetic interventions like 5-Amino-1MQ, BAM15, Humanin, L-Carnitine, Semaglutide, Tirzepatide, Retatrutide, and Tesofensine. The core takeaway is that SLU-PP-332 established a mechanistically compelling drug class for exercise-mimetic pharmacology, demonstrated consistent preclinical efficacy, and is limited in its current self-experimentation role by PK properties that are specifically addressed by the second-generation successor compound.

IUPAC Name

Not yet available

CAS Number

2264906-88-2

Molecular Formula

C23H20F3N3O4S2

Molecular Mass

535.54 g/mol

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