Abstract
SLU-PP-332 is a small molecule agonist of estrogen-related receptors (ERRα, ERRβ, ERRγ) under investigation for its ability to mimic certain metabolic and physiological effects of exercise. In rodent models of obesity and metabolic syndrome, SLU-PP-332 has demonstrated enhanced energy expenditure, improved insulin sensitivity, reduced adiposity, and upregulation of mitochondrial respiratory pathways. It may act via activation of mitochondrial biogenesis, fatty acid oxidation, and upregulation of oxidative phosphorylation genes. However, its safety, pharmacokinetics, off-target activity, and translational potential to humans remain largely unexplored. This paper reviews published preclinical data, mechanistic hypotheses, and key research gaps to guide future investigations.
Keywords / SEO Terms: SLU-PP-332, pan-ERR agonist, exercise mimetic, mitochondrial biogenesis, metabolic syndrome, ERRα agonist, CAS 303760-60-3, adiposity, insulin sensitivity, oxidative phosphorylation.
Introduction
Physical exercise exerts profound salutary effects on metabolism, mitochondrial health, insulin sensitivity, and systemic homeostasis. The capacity to pharmacologically replicate or augment “exercise-like” pathways — sometimes called exercise mimetics — is a compelling goal in metabolic research. Estrogen-related receptors (ERRs) — ERRα, ERRβ, ERRγ — are orphan nuclear receptors implicated in energy regulation, mitochondrial function, and oxidative metabolism.
SLU-PP-332 is a synthetic small molecule that acts as a pan-ERR agonist, with activity across all three isoforms. As a candidate exercise mimetic, SLU-PP-332 is being evaluated in preclinical models for its metabolic effects, including enhanced fat oxidation, mitochondrial upregulation, endurance, and insulin sensitivity. This research paper reviews the known biochemical, in vivo, and mechanistic data for SLU-PP-332, and outlines critical questions for future studies.
Chemical Identity & Physicochemical Properties
- CAS Number: 303760-60-3 Bio-Techne+1
- Chemical Name: (E)-4-Hydroxy-N’-(naphthalen-2-ylmethylene)benzohydrazide Tocris Bioscience+1
- Molecular Formula: C₁₈H₁₄N₂O₂ Bio-Techne+2Tocris Bioscience+2
- Molecular Weight: ~ 290.32 g/mol Bio-Techne+1
- Purity (catalog): ≥ 98% (HPLC) Tocris Bioscience+1
- Solubility: Highest solubility in DMSO (~100 mM) per vendor datasheet Tocris Bioscience
- Storage: Store at –20 °C, protected from moisture and light Bio-Techne+1
According to vendor catalogs (e.g. Tocris / Bio-Techne), SLU-PP-332 is described as a “potent pan-ERR agonist” with EC₅₀ values in the low to mid nanomolar range. Tocris Bioscience+1
Biological Activity & Preclinical Evidence
ERR Activation & Mechanistic Insights
SLU-PP-332 binds and activates ERRα, ERRβ, and ERRγ, with measured EC₅₀ values (approximate) of:
| Receptor | Approx. EC₅₀ |
|---|---|
| ERRα | ~98 nM Tocris Bioscience+1 |
| ERRβ | ~230 nM Tocris Bioscience |
| ERRγ | ~430 nM Tocris Bioscience+1 |
In vitro, SLU-PP-332 increases mitochondrial respiration and promotes oxidative metabolism pathways. Bio-Techne+2Tocris Bioscience+2
Activation of ERRs is associated with enhanced transcription of genes involved in mitochondrial biogenesis (e.g. TFAM), electron transport chain complexes, fatty acid β-oxidation (e.g. CPT1), and oxidative phosphorylation (OXPHOS). ERR activation is also known to cross-talk with PGC-1α and AMPK signaling axes, thereby amplifying metabolic reprogramming. (See review: Targeting ERRs in metabolic disorders). Wikipedia
In Vivo Animal Studies
- In a mouse model of metabolic syndrome, administration of SLU-PP-332 (dose and schedule according to vendor description) induced increased energy expenditure, elevated fatty acid oxidation, reduced fat mass, and improved insulin sensitivity. Bio-Techne+2Peptide Sciences+2
- Tocris catalog states that SLU-PP-332 in a metabolic syndrome mouse model decreases adipose accumulation and enhances mitochondrial respiration. Bio-Techne+1
- Peer-reviewed studies reported by Tocris: Billon et al. “Synthetic ERRα/β/γ agonist induces an ERRα-dependent acute aerobic exercise response and enhances exercise capacity” (ACS Chem. Biol.) and Billon et al. “A synthetic ERR agonist alleviates metabolic syndrome” (J Pharmacol Exp Ther) are cited by vendor as reference uses. Tocris Bioscience
- News release: “Exercise-mimicking drug sheds weight, boosts muscle activity in mice” describes that a novel drug in mice models showed improved metabolic endpoints. Although the news article does not always explicitly name SLU-PP-332, it is consistent with the concept. University of Florida News
These animal data suggest that SLU-PP-332 can partially recapitulate metabolic benefits of exercise (increased energy use, fat oxidation, mitochondrial enhancement) without necessarily augmenting food intake or requiring voluntary exercise.
Proposed Mechanisms of Action
Based on the convergence of ERR biology and preclinical data, plausible mechanistic pathways include:
- Mitochondrial biogenesis & function
SLU-PP-332 may stimulate new mitochondrial formation and enhance oxidative phosphorylation capacity, increasing baseline metabolic rate. - Fatty acid oxidation upregulation
Enhanced transcription of genes such as CPT1, MCAD, and others to facilitate β-oxidation of fatty acids, reducing lipid stores. - Interaction with PGC-1α / AMPK axis
ERR signaling often operates in concert with PGC-1α and AMPK to sense energy status; SLU-PP-332 may amplify these networks, mimicking low-energy or exercise states. - Muscle fiber remodeling & endurance adaptation
By promoting mitochondrial capacity and vascular density, SLU-PP-332 may shift fiber phenotype toward more oxidative types, improving endurance. - Glucose homeostasis modulation
Improved mitochondrial efficiency and substrate switching may contribute to better insulin sensitivity and glucose tolerance. - Cardiometabolic protection
In cardiac tissue, SLU-PP-332 may reduce fibrosis, preserve contractility, and support energy metabolism during stress.
These mechanisms remain hypothetical until validated with rigorous experiments (e.g. gene knockouts, dose–response, tissue-level assays, safety studies).
Limitations, Gaps & Risks
While promising, the current evidence is limited and there are significant gaps:
- Lack of published peer-reviewed human or clinical trial data — translation to humans is speculative.
- Pharmacokinetics / bioavailability are largely uncharacterized (absorption, metabolism, half-life, tissue distribution).
- Off-target effects / receptor promiscuity at higher concentrations may influence non-ERR nuclear receptors or other pathways.
- Safety and toxicity: no robust toxicology datasets in large animals publicly disclosed; observed mild adverse effects in animal studies may include hyperthermia, increased heart rate, altered liver enzymes (empiric vendor warnings).
- Dose optimization / therapeutic index unknown; narrow window may exist.
- Species differences: rodent ERR biology may not fully extrapolate to human ERR regulation.
- Long-term effects / chronic use unknown (mitochondrial overactivation, reactive oxygen species, cellular stress).
- Manufacturing, stability, and formulation challenges: chemical synthesis yield, purity, solubility, delivery systems.
Thus, rigorous future studies must address safety, pharmacology, dosing, efficacy, and translational biomarkers.
Future Directions & Research Agenda
To advance SLU-PP-332 from preclinical candidate to translational tool, the following priorities should be considered:
- Pharmacokinetic / pharmacodynamic (PK/PD) profiling in multiple species (rodents, non-rodents)
- Toxicology studies (acute, subchronic, chronic) including organ histopathology, genotoxicity, and safety margins
- Dose–response and potency optimization to define minimal effective dose and maximal tolerated dose
- Mechanistic validation via knockout or knockdown of ERR isoforms to confirm target engagement
- Biomarker development (e.g. mitochondrial gene expression, respiratory rates, circulating metabolites)
- Comparative studies vs exercise (e.g. exercise + SLU-PP-332 vs exercise alone)
- Exploration in disease models (obesity, insulin resistance, nonalcoholic fatty liver disease, cardiomyopathy, neurodegeneration)
- Combination therapy strategies with PPAR agonists, SIRT activators, or mitochondrial enhancers
- Formulation research (e.g. sustained release, nanoparticle delivery)
- Pilot human safety / proof-of-concept trials (once safety is acceptable in animals)
Conclusion
SLU-PP-332 is an intriguing pan-ERR agonist with early preclinical evidence suggesting it can recapitulate several metabolic benefits of exercise — enhancing mitochondrial function, increasing fat oxidation, improving insulin sensitivity, and reducing adiposity in rodents. Yet, substantial work remains before its translational potential to human therapy can be assessed. Its utility now is primarily as a research compound to probe ERR biology, mitochondrial regulation, and metabolic rewiring.
References (select)
- Tocris / Bio-Techne catalog — SLU-PP-332 technical data, purity, CAS, biological claims Tocris Bioscience+1
- PeptideSciences: SLU-PP-332 description — ERR activation, metabolic mimic claims Peptide Sciences+1
- Billon et al. “Synthetic ERRα/β/γ agonist … enhances exercise capacity” (cited by vendor) Tocris Bioscience
- Billon et al. “A synthetic ERR agonist alleviates metabolic syndrome” (cited) Tocris Bioscience
- News article: “Exercise-mimicking drug sheds weight, boosts muscle activity in mice” University of Florida News
- Review: Targeting ERRs in metabolic disorders: Opportunities and challenges (discusses ERR biology) Wikipedia
- Tocris description of activity in mouse models of metabolic syndrome Bio-Techne
Frequently Asked Questions (FAQ)
- What is SLU-PP-332?
SLU-PP-332 is a synthetic small molecule pan-agonist of estrogen-related receptors (ERRα, ERRβ, ERRγ), being studied as a potential exercise mimetic / metabolic modulator. - What is the CAS number of SLU-PP-332?
The CAS number is 303760-60-3. Bio-Techne+1 - How does SLU-PP-332 work mechanistically?
It binds to and activates ERR nuclear receptors, upregulating genes related to mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and metabolism, thereby promoting higher energy expenditure. - What preclinical effects have been observed in animal models?
In rodents, SLU-PP-332 increased energy expenditure, reduced fat mass, improved insulin sensitivity, and enhanced mitochondrial respiration in tissues. Peptide Sciences+3Bio-Techne+3Tocris Bioscience+3 - Has SLU-PP-332 been studied in humans or clinical trials?
As of now, there is no published evidence of human clinical trials with SLU-PP-332. Research is limited to preclinical studies and vendor claims. - Is SLU-PP-332 safe? What are the risks?
Safety in humans is unknown. In animals, potential risks include mild hyperthermia, changes in liver enzyme profiles, cardiovascular effects, and off-target receptor interactions. Rigorous toxicology data are lacking. - What are key challenges to translating SLU-PP-332 to human use?
Challenges include unknown pharmacokinetics, possible off-target effects, species differences, formulation stability, therapeutic margins, and regulatory approval pathways. - What diseases or conditions might SLU-PP-332 be relevant to?
Potential research applications include obesity, type 2 diabetes, metabolic syndrome, mitochondrial disorders, sarcopenia, cardiovascular disease, and neurodegeneration (hypothetically). - How should SLU-PP-332 be handled in laboratory settings?
Use as a research chemical only, with appropriate safety protocols. Store at –20 °C, protect from light/moisture, prepare stock solutions in DMSO or compatible solvent as per vendor solubility data. - What biomarkers or assays are useful to evaluate SLU-PP-332 effects?
Potential endpoints include mitochondrial respiration assays (e.g. Seahorse), gene expression of mitochondrial biogenesis markers (TFAM, PGC-1α), oxygen consumption, fatty acid oxidation flux, insulin tolerance tests, body composition metrics, and target engagement assays (ERR activation via reporter assays).
