SLU-PP-332

SLU-PP-332 (5mg): Compound Profile

SLU-PP-332 is categorized as an estrogen-related receptor agonist (ERR agonist). Initial testing in animal models has demonstrated three main outcomes:

• A rise in overall energy expenditure, mainly by increasing the rate of fat utilization.
• An improvement in physical endurance and exercise capacity.
• Higher mitochondrial density and efficiency, which optimizes muscle performance.

Introduction: The Need for an Exercise Mimetic

The numerous health benefits of regular exercise—such as disease prevention, mood improvement, and cognitive enhancement—are well-established. Yet, developing pharmaceuticals to reproduce these benefits has been challenging until recently, with the exception of peptide-based weight loss drugs like semaglutide. The new compound, SLU-PP-332, represents a breakthrough, successfully replicating some of exercise's positive effects. It acts as an ERR agonist, selectively targeting the alpha ($\alpha$) and gamma ($\gamma$) subclasses. Research suggests SLU-PP-332 boosts skeletal muscle stamina, aids in weight management, promotes heart health, and offers protection to the central nervous system against age and disease. Its ability to chemically mimic exercise effects makes it a significant development in research.

The Estrogen-Related Receptor (ERR) System

The receptors known as ERRs are not affected by estrogen, despite the historical basis for their name (the initial discovery of ERR$\alpha$ was due to its genetic similarity to the estrogen receptor).

ERRs are pivotal in controlling genes related to energy homeostasis, mitochondrial production, and oxidative metabolism. Their activation stimulates energy use and boosts the breakdown of fatty acids, promoting fat loss. They also enhance mitochondrial function, especially in muscle tissues, which is key for endurance and cardiovascular health.

The crucial role of ERRs in physical capacity was confirmed in studies using knockout mice—animals genetically missing specific ERR genes in their muscle, resulting in a severe inability to endure exercise. ERR$\alpha$ and ERR$\gamma$ are the most critical for endurance, with deficient mice showing reduced oxidative capacity and an inability to shift to fat metabolism for sustained effort.

• ERR$\alpha$ regulates genes for fatty acid metabolism, gluconeogenesis, and thermogenesis, and influences various metabolic markers. It's essential for physiological stress adaptation and is a known target of statins.
• ERR$\gamma$ regulates mitochondrial activity and gene transcription. It is a major binding target for the endocrine disruptor bisphenol A (BPA), an interaction thought to underlie BPA's link to metabolic syndrome and cancer. It is also being studied for its neuroprotective potential in Parkinson's disease, as its activation may mitigate toxicity, making agonists like SLU-PP-332 a therapeutic focus.
• ERR$\beta$ is the least understood, mainly involved in regulating stem cell development for tissue regeneration.

Research and Drug Properties

The ability of SLU-PP-332 to distribute effectively to ERRs across the body after injection (bioavailability) is a core feature, making it suitable for in vivo research (studies in living organisms). Previous ERR agonists were mainly limited to in vitro (non-living) studies due to stability issues or poor target access. SLU-PP-332 is one of the few to show efficacy in living cells with an acceptable safety profile. Furthermore, its successful synthesis as a functional ERR$\alpha$ agonist—a subtype previously difficult to target—is a major scientific milestone, accelerating the pursuit of exercise mimetics.

Systemic Effects of SLU-PP-332

1. Musculoskeletal & Endurance

The search for an exercise mimetic is fueled by the widespread difficulty in maintaining exercise habits. While GHRH agonists (e.g., Sermorelin) and BDNF-boosting peptides (e.g., Selank) replicate some benefits, SLU-PP-332 is notable for addressing the fundamental, cellular benefit of exercise: enhancing cellular respiration and mitochondrial function. Exercise naturally boosts the quantity and efficiency of these cellular "powerhouses," leading to higher metabolism, better stamina, and improved cardiovascular health. SLU-PP-332 directly promotes these same mitochondrial adaptations.

• Endurance Boost: Activating ERR$\gamma$ significantly increases mitochondrial density in muscle cells, boosting energy production and fatigue resistance. This activation also promotes new blood vessel growth (vascularization), which enhances performance by optimizing oxygen/nutrient exchange and is linked to better insulin sensitivity. Treated mice ran 70% longer and 45% farther, an effect supported by enhanced cellular energy and greater fat utilization.
• Muscle Adaptation: SLU-PP-332 mimics the body's natural response to exercise, which is to increase ERR expression in muscle tissue to improve efficiency, thereby enhancing function without physical exertion.

2. Cardiovascular Health

As a pan-ERR agonist (activating all three subtypes), SLU-PP-332 has shown promise in heart failure models by improving the heart’s pumping efficiency (ejection fraction), reducing cardiac fibrosis (scarring), and increasing survival rates. Its ability to normalize heart tissue energy balance makes it a potential therapeutic agent, as reducing fibrosis is key to maintaining heart function.

3. Neurological Health (Parkinson's)

Parkinson's disease is characterized by the loss of neurons and the formation of Lewy bodies. The affected neurons are highly vulnerable to mitochondrial dysfunction and energy failure, which is a core pathology of the disease. By enhancing mitochondrial activity through ERR$\gamma$ activation, SLU-PP-332 offers a promising path for neuroprotection. ERR$\gamma$ is a key regulator of neuronal metabolism and health, including autophagy.

4. Renal Function and Anti-Aging

The high metabolic rate of the kidney makes it sensitive to age-related decline, which is accelerated by metabolic diseases that cause inflammation and mitochondrial damage. Caloric restriction, a proven anti-aging intervention, prevents the age-related drop in ERR levels. SLU-PP-332, through its ERR$\alpha$ activity, effectively mimics the protective renal effects of caloric restriction—reducing inflammation and protecting mitochondrial function—without dietary restriction. Preserving mitochondrial health is a central anti-aging strategy, as its decline is a source of damaging free radicals.

Related Compounds and Summary

SLU-PP-1072 and SLU-PP-915 are the other main ERR agonists. SLU-PP-1072 (targets $\alpha$/$\gamma$) is studied for prostate cancer, while SLU-PP-915 is studied for heart failure, showing similar benefits to SLU-PP-332.

In summary, SLU-PP-332 primarily targets ERR$\alpha$ and ERR$\gamma$, enhancing mitochondrial energy capacity and reducing oxidative stress, leading to better endurance. Early research is encouraging for its potential in heart, kidney, and brain health.

Article Author: Dr. Daniel P. Kelly, M.D., Director of the Center for Cardiovascular Research at Washington University School of Medicine.

Scientific Journal Author: Dr. Vincent Giguère, Ph.D., an acclaimed molecular endocrinologist at McGill University specializing in ERR biology and metabolism, is cited as a key source. The citation does not constitute an endorsement.