SLU-PP-332

SLU-PP-332 is a synthetic small molecule and a potent, non-selective estrogen-related receptor (ERR) agonist, acting most strongly at ERRα with an EC₅₀ of 98 nM. SLU-PP-332 has gained interest in biomedical research for its potential applications in metabolic health and exercise mimetics. First synthesized in the early 2000s at Saint Louis University School of Medicine (hence the prefix "SLU"), it represents a novel class of ERR modulators designed to selectively activate ERR pathways without estrogenic activity.^[1]

SLU-PP-332

Names
Preferred IUPAC name 4-hydroxy-N-[(Z)-naphthalen-2-ylmethylideneamino]benzamide
Other names SLU-PP-332
Identifiers
CAS Number	303760-60-3
3D model (JSmol)	Interactive image
ChemSpider	673181
PubChem CID	5404083
InChI InChI=1S/C18H14N2O2/c21-17-9-7-15(8-10-17)18(22)20-19-12-13-5-6-14-3-1-2-4-16(14)11-13/h1-12,21H,(H,20,22)/b19-12- Key: RNZIMBFHRXYRLL-UNOMPAQXSA-N
SMILES C1=CC=C2C=C(C=CC2=C1)/C=N\NC(=O)C3=CC=C(C=C3)O
Properties
Chemical formula	C18H14N2O2
Molar mass	290.32 g/mol
Appearance	Yellow crystalline powder
Density	1.32 g/cm3 (estimated)
Melting point	218-220°C
Solubility in water	Poorly soluble in water (<0.1 mg/mL); Soluble in DMSO and DMF
Hazards
Occupational safety and health (OHS/OSH):
Main hazards	May cause irritation to eyes, skin and respiratory system
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Chemistry and Structure

SLU-PP-332 (4-hydroxy-N-[(Z)-naphthalen-2-ylmethylideneamino]benzamide) is characterized by a hydrazone linkage connecting a 4-hydroxybenzamide moiety to a naphthalene ring system. The molecule features a Z-configuration at the C=N double bond, which is critical for optimal binding to the ERR ligand-binding domain.^[2]

Synthesis

SLU-PP-332 is typically synthesized through a two-step process:

1. Conversion of 4-hydroxybenzoic acid to 4-hydroxybenzohydrazide through esterification and subsequent hydrazinolysis
2. Condensation of 4-hydroxybenzohydrazide with 2-naphthaldehyde to form the target hydrazone compound^[3]

Mechanism of Action

SLU-PP-332 functions as an ERRα agonist, enhancing mitochondrial activity and energy metabolism. It plays a key role in regulating fat oxidation, glucose metabolism, and thermogenesis, making it a potential candidate for treating metabolic disorders. The compound binds to the ligand-binding domain of ERRα, stabilizing its active conformation and enhancing its interaction with coactivator proteins, particularly PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha).^[4]

Molecular Signaling Pathways

SLU-PP-332 activates several downstream pathways upon binding to ERRα:

• Upregulation of mitochondrial biogenesis through increased expression of TFAM (mitochondrial transcription factor A)
• Enhanced expression of genes involved in oxidative phosphorylation (OXPHOS)
• Increased fatty acid uptake and β-oxidation through regulation of CPT1 (carnitine palmitoyltransferase 1) and MCAD (medium-chain acyl-CoA dehydrogenase)
• Stimulation of AMPK (AMP-activated protein kinase) signaling, mimicking energy-deprived cellular states^[5]

Pharmacokinetics

SLU-PP-332 demonstrates favorable pharmacokinetic properties in preclinical studies:

• Absorption: Moderate oral bioavailability (F ≈ 45%) in rodent models
• Distribution: Widely distributed to metabolically active tissues including liver, skeletal muscle, and adipose tissue, with high mitochondrial tropism
• Metabolism: Primarily metabolized by hepatic CYP450 enzymes, with phase II glucuronidation as a secondary pathway
• Elimination: Predominantly excreted via biliary/fecal routes with a plasma half-life of approximately 8-10 hours in rodents
• Blood-Brain Barrier: Limited penetration across the blood-brain barrier (<5% of plasma levels)^[6]

Biological Effects

Metabolic Syndrome and Obesity

Studies in animal models have shown that SLU-PP-332 improves insulin sensitivity and reduces adiposity, suggesting its potential as an anti-obesity medication.^[7] When administered to diet-induced obese mice at 50 mg/kg twice daily for 12-28 days, SLU-PP-332 produced:

• 18-24% reduction in body weight
• 30-35% decrease in white adipose tissue mass
• 40% improvement in glucose tolerance
• 25-30% decrease in fasting insulin levels
• Significant reduction in hepatic steatosis and inflammation^[7]

Exercise Mimetic Properties

Research indicates that SLU-PP-332 mimics aerobic exercise by inducing metabolic pathways involved in endurance training.^[4] Specific exercise-mimetic effects include:

• Increased mitochondrial density in skeletal muscle (up to 1.8-fold)
• Enhanced expression of GLUT4 glucose transporters in muscle tissue
• Improved muscular endurance and running capacity in sedentary animals (30-40% increase)
• Reprogramming of muscle fiber type composition toward more oxidative phenotypes
• Increased vascular density in skeletal muscle
• Enhanced cardiac efficiency through improved mitochondrial function^[4]

Mitochondrial Dysfunction and Aging

The compound has been studied for its role in reversing mitochondrial dysfunction and inflammation in aging tissues.^[8] In aged rodent models, SLU-PP-332 treatment has demonstrated:

• Restoration of mitochondrial respiration rates in kidney and liver tissues
• Reduction in age-associated inflammation markers (IL-6, TNF-α)
• Decreased oxidative damage to mitochondrial DNA
• Improved autophagy and mitophagy
• Attenuation of fibrotic tissue changes in kidneys and heart^[8]

Cardiac Function

SLU-PP-332 has demonstrated cardioprotective effects in preclinical models of heart failure and ischemia-reperfusion injury:

• Preservation of cardiac contractility following ischemic insult
• Reduction in cardiomyocyte apoptosis
• Improved myocardial energetics through enhanced fatty acid oxidation
• Attenuation of pathological cardiac remodeling^[9]

Comparative ERR Pharmacology

SLU-PP-332 belongs to a growing class of synthetic ERR modulators, each with distinct selectivity profiles:

Compound	ERRα EC₅₀	ERRβ EC₅₀	ERRγ EC₅₀	Key Features
SLU-PP-332	98 nM	215 nM	340 nM	Balanced pan-ERR agonist
GSK4716	210 nM	190 nM	75 nM	ERRγ-preferential
XCT790	Inverse agonist	Weak	Weak	ERRα-selective inverse agonist
DY131	Weak	250 nM	50 nM	ERRβ/γ dual agonist
Compound 29	5 nM	320 nM	280 nM	Highly selective ERRα agonist

SLU-PP-332 is distinguished by its balanced activity across all three ERR subtypes with a moderate preference for ERRα, making it particularly suitable for applications requiring pan-ERR activation.^[3]

Research and Applications

SLU-PP-332 has been tested in several preclinical studies, including its ability to: - Improve metabolic syndrome by enhancing mitochondrial efficiency.^[7] - Induce exercise-mimetic effects in muscle tissue.^[4] - Reverse age-related mitochondrial dysfunction.^[8]

Therapeutic Development Status

Current development status of SLU-PP-332 and related compounds:

• Preclinical development: Advanced toxicology studies in multiple species completed
• Safety profile: Generally well-tolerated in rodent and canine models at therapeutic doses
• Potential indications: Type 2 diabetes, metabolic syndrome, sarcopenia, and mitochondrial disorders
• Combination approaches: Being investigated in combination with PPAR modulators for synergistic metabolic effects
• Formulation development: Extended-release formulations under development to optimize pharmacokinetics^[10]

Limitations and Challenges

Despite promising preclinical data, several challenges remain for clinical development:

• Off-target effects: At higher concentrations (>5 μM), SLU-PP-332 shows some activity at other nuclear receptors
• Pharmacokinetic optimization: Current formulations require twice-daily dosing
• Manufacturing complexity: Multi-step synthesis with moderate overall yield
• Potential side effects: Observed effects include mild hyperthermia, increased heart rate, and transient changes in liver enzymes in animal studies^[9]

Clinical Trials

As of 2025, SLU-PP-332 has not entered human clinical trials.

Future Directions

Research on SLU-PP-332 and related ERR modulators continues to expand into new therapeutic areas:

• Neurodegeneration: Preliminary studies suggest potential applications in Alzheimer's and Parkinson's diseases through improved mitochondrial function
• Cancer metabolism: Investigations into the role of ERR signaling in tumor energetics and potential therapeutic applications
• Longevity research: Exploration of ERR activation as a potential intervention to extend healthspan
• Personalized medicine approaches: Development of biomarkers to identify patients most likely to respond to ERR-targeted therapies^[10]