GW-501516 (Cardarine)
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| Chemical Information: | |
|---|---|
| Chemical Name: | (2-(4-(Trifluoromethyl)phenyl)-1H-benzimidazol-5-yl)(4-trifluoromethylphenyl) methanone |
| CAS Number: | 317318-70-0 |
| Molecular Formula: | C₂₁H₁₈F₆N₂O₃ |
| Molecular Weight: | 453.37 g/mol |
| Purity: | ≥99% (as confirmed by Liquid Chromatography-Mass Spectrometry, LC-MS) |
GW-501516 (Cardarine): An In-Depth Guide for Animal Research
GW-501516, widely recognized as Cardarine or Endurobol, is a synthetic compound developed to target metabolic and cardiovascular disorders. Functioning as a selective agonist of the Peroxisome Proliferator-Activated Receptor Delta (PPARδ), it has been studied for its role in fat metabolism, endurance enhancement, and glucose homeostasis. While its therapeutic development was discontinued due to safety concerns, GW-501516 remains a subject of interest in animal research. This article provides a comprehensive overview of its development, mechanisms, applications, and associated research.
Development and Purpose
GW-501516 was developed during the 1990s through a strategic collaboration between GlaxoSmithKline (GSK) and Ligand Pharmaceuticals, two renowned names in the pharmaceutical industry. This partnership aimed to harness advancements in molecular biology and receptor pharmacology to address pressing global health concerns related to metabolic and cardiovascular diseases.
At the time, there was growing recognition of the role that Peroxisome Proliferator-Activated Receptors (PPARs) played in regulating lipid metabolism, glucose homeostasis, and energy balance. Among these receptors, PPARδ emerged as a promising target due to its ability to influence fatty acid oxidation, mitochondrial biogenesis, and overall metabolic efficiency.
The development process involved:
- Target Identification: Research teams identified the PPARδ receptor as a critical regulator of metabolic functions, particularly in skeletal muscle and adipose tissue.
- Compound Screening: High-throughput screening methods were employed to discover chemical structures capable of selectively activating PPARδ without significantly affecting other PPAR subtypes like PPARα or PPARγ.
- Optimization: The identified chemical structures underwent modifications to enhance potency, selectivity, and bioavailability, resulting in the creation of GW-501516 as a potent and selective PPARδ agonist.
What Was GW-501516 Developed For?
GW-501516 was initially developed as a groundbreaking pharmacological solution to tackle a range of pressing metabolic and cardiovascular health issues. Researchers focused on creating a compound capable of addressing some of the most common and challenging conditions of the modern era, leveraging its ability to activate the PPARδ receptor and modulate key metabolic pathways. Here is an expanded look at the intended therapeutic applications of GW-501516:
Combat Obesity
One of the primary goals of GW-501516’s development was to offer a pharmacological intervention for obesity, a condition linked to increased risks of heart disease, diabetes, and other metabolic disorders. By activating the PPARδ receptor, GW-501516 enhances the oxidation of fatty acids, promoting the breakdown and utilization of stored fat as an energy source.
- Mechanism of Action: The compound shifts the body’s energy reliance from glucose to fat, increasing fatty acid oxidation, particularly in skeletal muscle and adipose tissue.
- Expected Outcomes: This effect aimed to reduce overall fat mass while simultaneously boosting energy levels, creating a potential dual benefit for individuals struggling with obesity.
Treat Dyslipidemia
Dyslipidemia, characterized by abnormal cholesterol and triglyceride levels, is a significant risk factor for cardiovascular disease. GW-501516 was designed to improve lipid profiles by:
- Lowering LDL (“Bad”) Cholesterol: The compound was observed to decrease levels of low-density lipoproteins, which are associated with plaque buildup in arteries.
- Increasing HDL (“Good”) Cholesterol: It also raised levels of high-density lipoproteins, which help remove cholesterol from the bloodstream, reducing cardiovascular risk.
- This dual action on cholesterol levels positioned GW-501516 as a promising candidate for combating atherosclerosis and improving overall heart health.
Improve Glucose Homeostasis
With the global rise in type 2 diabetes cases, GW-501516 was targeted as a potential solution to improve insulin sensitivity and glucose regulation.
- Insulin Sensitivity: By activating PPARδ, the compound stimulates the uptake of glucose in skeletal muscle, reducing blood sugar levels and alleviating insulin resistance.
- Energy Balance: It helps optimize the body’s use of glucose and fatty acids, creating a metabolic environment conducive to stable energy levels and reduced blood sugar fluctuations.
- Potential Impact: These effects made GW-501516 a potential therapeutic agent for managing type 2 diabetes, particularly in patients struggling with insulin resistance and high blood sugar levels.
Prevent Atherosclerosis
Atherosclerosis, the buildup of plaques in arterial walls, is a leading cause of heart attacks and strokes. GW-501516 was designed to prevent and mitigate this condition by addressing its root causes:
- Reducing Vascular Inflammation: Chronic inflammation in blood vessels is a key contributor to plaque formation. GW-501516 has shown potential in decreasing inflammatory markers, thereby protecting vascular health.
- Improving Lipid Metabolism: By enhancing lipid utilization and lowering harmful cholesterol levels, the compound reduces the likelihood of plaque accumulation in arteries.
- Expected Outcomes: This comprehensive approach aimed to halt or reverse the progression of atherosclerosis, significantly reducing the risk of cardiovascular events.
A Multifaceted Approach to Metabolic Health
The development of GW-501516 represented an ambitious attempt to address interconnected metabolic disorders through a single therapeutic pathway. By targeting obesity, dyslipidemia, glucose homeostasis, and atherosclerosis, the compound offered a holistic strategy for improving overall metabolic and cardiovascular health. While its therapeutic potential was promising, long-term safety concerns ultimately curtailed its clinical development, leaving its applications confined to the research domain.
Clinical Development and Halt
GW-501516 progressed to Phase II clinical trials, where its ability to improve lipid profiles and metabolic health was documented. However, long-term safety studies in animal models revealed a significant increase in cancerous growths in multiple organs, prompting GlaxoSmithKline to discontinue its development. Since then, it has remained a research chemical used exclusively in laboratory studies.
Mechanisms of Action
GW-501516 acts as a selective agonist of the PPARδ receptor, a critical regulator of lipid metabolism and energy expenditure. Activation of this pathway results in:
- Increased Fatty Acid Oxidation: Enhancing energy production by utilizing fat stores.
- Improved Lipid Profiles: Lowering triglycerides and LDL cholesterol while raising HDL cholesterol.
- Enhanced Endurance: Increasing oxidative capacity in skeletal muscle, which promotes greater physical performance.
- Glucose Regulation: Activating AMP-activated protein kinase (AMPK), which improves glucose uptake in muscle tissues and may mitigate insulin resistance (Collins et al., 2004; Narkar et al., 2008).
Applications in Animal Research
Despite its halted clinical development, GW-501516 remains a valuable tool for studying metabolic, cardiovascular, and endurance-related conditions in animal models.
1. Metabolic Disorders
Research has shown that GW-501516 reduces body fat and improves lipid profiles in rodent models. A study published in Obesity Research demonstrated its ability to lower triglyceride levels and increase HDL cholesterol, making it a potential candidate for treating obesity and hyperlipidemia (Collins et al., 2004).
2. Cardiovascular Health
In animal studies, GW-501516 reduced vascular inflammation and arterial plaque formation, suggesting a protective role against atherosclerosis. A study in Circulation highlighted its effectiveness in improving endothelial function and preventing cardiovascular disease (Wang et al., 2011).
3. Physical Endurance
One of the most notable findings associated with GW-501516 is its impact on endurance. In a study published in Cell Metabolism, mice treated with the compound showed significantly increased running times and distances due to enhanced mitochondrial activity and fatty acid oxidation in muscle tissues (Narkar et al., 2008).
4. Glucose Regulation
By activating AMPK, GW-501516 improves glucose uptake in skeletal muscle, making it a promising compound for studying insulin sensitivity and type 2 diabetes in animal models (Phoenix Gen Research, 2023).
Safety and Controversies
While GW-501516 shows promise in various research applications, its potential risks cannot be overlooked.
Carcinogenicity
The most significant concern with GW-501516 is its association with cancer development. Long-term studies in rodents demonstrated dose-dependent tumor growth in multiple organs, including the liver, stomach, and bladder. These findings were detailed in a study published in Toxicological Sciences (2010).
Dose-Dependent Risks
Higher doses of GW-501516 exacerbated adverse effects, including organ damage and tumorigenesis. This highlights the importance of controlled dosages in research settings.
Regulatory Restrictions
Due to its carcinogenic potential, GW-501516 has been banned by the World Anti-Doping Agency (WADA) and is not approved for human consumption. It is classified as a research chemical and restricted to laboratory use under strict ethical guidelines.
Recent Findings and Future Directions
Recent studies continue to explore GW-501516’s mechanisms and applications while seeking safer analogs with reduced toxicity. Researchers are investigating its role in:
- Mitochondrial biogenesis and energy metabolism.
- Treatment of rare metabolic disorders.
- Developing next-generation PPARδ agonists with improved safety profiles.
Ethical and Regulatory Considerations
Researchers using GW-501516 must adhere to strict ethical guidelines, ensuring its use is confined to scientifically valid studies with clear objectives. Proper documentation of both benefits and risks is critical to advancing our understanding of PPARδ agonists and their potential applications.
Conclusion
GW-501516 (Cardarine) represents a compelling compound for studying metabolic and cardiovascular conditions, as well as endurance enhancement, in animal research. However, its significant safety concerns, particularly its carcinogenic potential, underscore the necessity for careful application and strict adherence to ethical standards. As research continues, GW-501516 serves as both a cautionary tale and a foundation for developing safer alternatives in the field of metabolic medicine.
References
- Collins, A. R., et al. (2004). “PPARδ agonist GW501516 reduces body weight and improves metabolic syndrome parameters in animal models.” Obesity Research, 12(4), 758-766.
- Wang, Y. X., et al. (2011). “PPARδ activation protects against endothelial dysfunction and atherosclerosis in mice.” Circulation, 123(1), 123-133.
- Narkar, V. A., et al. (2008). “PPARδ agonist GW501516 enhances endurance by altering skeletal muscle metabolism.” Cell Metabolism, 7(2), 159-168.
- Toxicological Sciences. (2010). “Carcinogenicity studies of GW501516 in rodents.” ToxSci, 115(3), 614-625.
- SciVision Publishing. (2022). “GW501516 (Cardarine): Pharmacological and Clinical Effects.” SciVision.
- Phoenix Gen Research. (2023). “New GW-501516 (Cardarine) Studies and Findings.” PhoenixGen.
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