GW0742: A Comprehensive Guide to the PPARβ/δ Agonist and Its Therapeutic Applications

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In the realm of metabolic research, few compounds have garnered as much scientific attention as GW0742. This research chemical, also known as GW610742 and fitorine, represents a breakthrough in understanding peroxisome proliferator activated receptor β δ (PPARβ/δ) modulation. As part of a class of selective small molecule agonists, GW0742 is widely used to study specific receptor activation and metabolic regulation. Originally developed by GlaxoSmithKline, GW0742 has become an invaluable tool for researchers investigating lipid metabolism, energy homeostasis, and cardiovascular function in laboratory settings.

Research suggests that this selective small molecule agonist offers unprecedented insights into nuclear receptor biology, making it a cornerstone compound for metabolic research applications. As scientists continue to explore its mechanisms and applications, GW0742 remains strictly designated for research use only, providing researchers with a powerful tool to advance our understanding of metabolic diseases and vascular biology.

What is GW0742?

GW0742 functions as a potent and highly selective peroxisome proliferator activated receptor β δ agonist, demonstrating remarkable specificity for this particular nuclear receptor. Research indicates that this compound exhibits an EC50 of approximately 1-1.1 nM for PPARβ/δ, showing over 1000-fold selectivity compared to the closely related PPARα and PPARγ isoforms.

The compound’s molecular structure consists of a complex arrangement with the molecular formula C21H17F4NO3S2 and a molecular weight of approximately 471.48 g/mol. Its IUPAC name is 2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-thiazol-5-ylmethylthio]-2-methylphenoxyacetic acid, reflecting its sophisticated chemical architecture.

Property	Value
Molecular Weight	471.48 g/mol
EC50 for PPARβ/δ	1-1.1 nM
Selectivity	>1000-fold vs PPARα/γ
Water Solubility	Insoluble
DMSO Solubility	Up to 86 mg/mL

As a research chemical, GW0742 is typically available at high purity (>98-99% by HPLC) and requires specific handling protocols. The compound is insoluble in water but can be dissolved in DMSO or ethanol for experimental applications, making it suitable for various in vitro and in vivo research protocols. Studies have shown that GW0742 is effective via intravenous injection but does not significantly alter blood glucose levels when administered through oral administration, underscoring the importance of pharmacokinetic considerations such as absorption and bioavailability for oral delivery.

Mechanism of Action of Peroxisome Proliferator Activated Receptor

Research demonstrates that GW0742 activates the peroxisome proliferator activated receptor δ through high-affinity binding, leading to transcriptional modulation of target genes involved in fatty acid oxidation and energy metabolism. Studies suggest that this activated receptor delta plays a key role in promoting tissue regeneration, modulating inflammatory responses, and improving metabolic functions, in addition to enhancing fatty acid oxidation pathways while simultaneously reducing hepatic lipogenesis.

The biological activity of this selective agonist extends to the upregulation of key enzymes involved in mitochondrial function, including CPT1A (carnitine palmitoyltransferase 1A) and CACT (carnitine/acylcarnitine translocase). Research indicates that these enzymes are crucial components of the mitochondrial beta-oxidation pathway, facilitating the efficient metabolism of fatty acids.

Laboratory studies have shown that GW0742’s effects on endothelial cell tubulogenesis are enhanced by SIRT1, indicating cofactor dependency for specific cellular outcomes. This finding suggests that the compound’s mechanisms involve complex interactions with cellular cofactors and metabolic networks.

At the molecular level, research suggests that this δ agonist influences gene expression patterns associated with:

• Fatty acid metabolism and oxidation
• Glucose uptake mechanisms
• Mitochondrial biogenesis
• Cellular energy homeostasis
• Inflammatory response modulation

Studies have revealed that GW0742 can exhibit mixed agonist/antagonist behavior at varied concentrations and shows weak off-target activity on other nuclear receptors, including antagonistic effects at the androgen receptor and vitamin D receptor.

Metabolic Benefits, Lipid Metabolism, and Applications

Research conducted in diet induced obese mice has demonstrated that GW0742 administration can reduce body mass without altering overall energy intake, suggesting that its metabolic effects stem from enhanced energy metabolism rather than appetite suppression. Notably, GW0742 has been shown to enhance lipid metabolism by promoting lipid utilization and supporting metabolic health in experimental models. These findings indicate significant potential for studying metabolic regulation in laboratory settings.

Studies in diabetic models have shown that this selective ppar δ agonist improves glucose homeostasis and reduces insulin resistance, as measured by decreased HOMA-IR scores. Research suggests that these improvements in insulin sensitivity occur through enhanced glucose uptake mechanisms in skeletal muscle tissue, where the compound upregulates GLUT4 expression.

Laboratory investigations have revealed that GW0742 alleviates endoplasmic reticulum stress in liver tissue under high fat diet conditions. Research indicates that the compound promotes a shift in hepatic metabolism from lipogenesis toward beta-oxidation, potentially protecting against non-alcoholic fatty liver disease development in experimental models.

Key metabolic research applications include:

• Obesity Studies: Diet induced obesity models using C57BL/6 mice
• Diabetes Research: Streptozotocin-induced type 1 diabetes models
• Insulin Sensitivity: Hyperinsulinemic-euglycemic clamp studies
• Liver Function: High-fat diet-induced hepatic dysfunction models
• Metabolic Syndrome: Fructose-rich diet models for insulin resistance

Research has also demonstrated protective effects against pancreatitis in experimental models, suggesting broader applications in studying inflammatory conditions affecting metabolic organs.

Cardiovascular and Vascular Effects

Studies investigating cardiovascular research applications have shown that GW0742 reduces vascular inflammatory responses and improves endothelial dysfunction in diabetic mice. Research suggests that pharmacological activation of PPARβ/δ leads to direct protective effects on blood vessels, particularly in models of metabolic stress.

Laboratory investigations have demonstrated that this compound prevents hypertension in diet induced obese mice and provides protection in various models of cardiovascular complications. Research indicates specific benefits in models of hypoxia induced pulmonary hypertension and acute lung injury, suggesting potential applications in studying pulmonary vessels and vascular remodeling.

In cell culture studies using human umbilical vein endothelial cells (HUVECs), research has shown that GW0742 stimulates angiogenesis and tubulogenesis, particularly when SIRT1 activity is present. Notably, the δ agonist GW0742 has been shown to influence endothelial cell metabolism, angiogenic behavior, and protective vascular functions by acting as a selective PPARβ/δ agonist, affecting metabolic pathways such as fatty acid oxidation and glycolysis during different stages of angiogenesis and tissue protection. These findings suggest applications in studying:

• Endothelial cell function and metabolism
• Angiogenesis mechanisms
• Vascular inflammatory responses
• Tissue regeneration processes
• Affecting vascular remodeling pathways

Studies have also revealed enhanced myonuclear accretion and fiber remodeling in mouse skeletal muscle, along with cardioprotective effects through reduction of cardiac hypertrophy. Research suggests that these effects contribute to maintaining muscle mass and improving physical endurance in experimental models.

Effects on Diabetic Models

GW0742 has demonstrated significant benefits in diabetic models, particularly in diet induced obese mice and diabetic rats. By activating pparβ δ, this compound enhances lipid metabolism and promotes fatty acid oxidation in mouse skeletal muscle and cardiac tissue. These effects lead to marked improvements in insulin sensitivity, a key factor in managing insulin resistance commonly observed in diabetic models.

Research in diet induced obese mice has shown that GW0742 administration results in reduced body weight and body mass, outcomes closely linked to its ability to modulate lipid metabolism and regulate the immune response. In addition, studies indicate that GW0742 helps prevent skeletal muscle inflammation triggered by high sugar intake, further supporting its role in improving metabolic health.

In diabetic rats, GW0742’s activation of pparβ δ not only improves insulin sensitivity but also supports healthy fatty acid metabolism in skeletal muscle, contributing to better glucose regulation. These findings underscore the compound’s potential for addressing insulin resistance and metabolic dysfunction in a range of diabetic models, making it a valuable tool for researchers investigating the interplay between lipid metabolism, immune response, and metabolic disease progression.

Effects on Body Composition

GW0742 has been shown to positively influence body composition in both diet induced obese mice and diabetic rats. Through its modulation of lipid metabolism and enhancement of fatty acid oxidation in skeletal muscle, GW0742 effectively reduces body weight and body mass in these experimental models. This reduction is achieved without compromising muscle mass, as the compound supports the maintenance of lean tissue even during periods of metabolic stress.

One of the key mechanisms underlying these effects is GW0742’s ability to enhance glucose uptake in skeletal muscle, which not only aids in maintaining muscle mass but also contributes to improved overall metabolic health. By supporting efficient fatty acid utilization and regulating the immune response, GW0742 helps to create a metabolic environment conducive to healthy body composition, particularly in obese mice and diabetic rats.

These findings highlight the compound’s potential for research into interventions aimed at reducing excess body fat while preserving muscle mass, a critical consideration in the management of metabolic diseases and obesity-related complications.

Research Applications and Studies

GW0742 has been extensively utilized in fundamental and translational research, particularly in C57BL/6 mouse models for obesity and diabetes studies. Research protocols commonly employ this compound in hyperinsulinemic-euglycemic clamp studies to assess insulin sensitivity and glucose metabolism in controlled laboratory conditions.

Streptozotocin-induced models of type 1 diabetes serve as primary experimental systems for evaluating pancreatic islet function and metabolic regulation. Research suggests that these models provide valuable insights into glucose homeostasis and insulin resistance mechanisms when combined with GW0742 treatment protocols.

Human umbilical vein endothelial cell (HUVEC) cultures represent the primary in vitro model for investigating the compound’s role in angiogenesis and vascular biology. Studies utilizing these cell systems have revealed important mechanisms of endothelial metabolism and tubulogenesis.

Additional research applications include:

Model System	Research Focus	Key Findings
Zucker fatty rats	Obesity and metabolism	Enhanced fatty acid oxidation
Diabetic rats	Glucose homeostasis	Improved insulin sensitivity
Pulmonary artery banding	Cardiovascular function	Reduced pulmonary hypertension
High sugar intake models	Metabolic syndrome	Improved metabolic regulation

Research has also employed fructose-rich diet models to simulate and study type 2 diabetes-like insulin resistance, providing valuable insights into metabolic diseases and their underlying mechanisms.

Molecular Targets and Pathways

At the molecular level, research demonstrates that GW0742 upregulates GLUT4 expression in skeletal muscle tissue, facilitating increased glucose uptake into muscle fibers. Studies suggest that this mechanism contributes significantly to improving insulin sensitivity in experimental models.

Laboratory investigations have shown that the compound decreases hepatic PEPCK (phosphoenolpyruvate carboxykinase) expression, a key enzyme in gluconeogenesis. Research indicates that this decreased expression results in lower endogenous glucose production and improved glycemic control in diabetic models.

The compound’s effects extend to genes associated with mitochondrial function and biogenesis, including:

• LDHA (lactate dehydrogenase A): Metabolic enzyme regulation
• MCT1 (monocarboxylate transporter 1): Cellular transport mechanisms
• MFN2 (mitofusin-2): Mitochondrial fusion and biogenesis
• CPT1A: Key enzymes involved in fatty acid oxidation
• CACT: Carnitine transport mechanisms

Research suggests that these molecular targets collectively influence cellular energy metabolism and mitochondrial health. Studies have revealed that endothelial cell response to GW0742 requires intact glycolytic pathways, highlighting the need for coordinated metabolic networks.

The compound also modulates cytokine production and immune response pathways, with research indicating enhanced production of anti inflammatory cytokines in certain experimental conditions. These findings suggest broader applications in studying inflammation and immune regulation.

Experimental Methods and Protocols

Research protocols commonly dissolve GW0742 in DMSO for in vitro studies, achieving concentrations up to 86 mg/mL (182.39 mM at 25°C), or in ethanol at concentrations up to 40 mg/mL (84.84 mM). For in vivo studies, the compound is typically administered using 2% DMSO plus solubilizing agents to ensure uniform exposure and bioavailability.

Laboratory studies utilize low micromolar concentrations in cell culture applications, with research suggesting optimal effectiveness in this concentration range. The specificity of action can be confirmed through co-treatment with the PPARβ/δ antagonist GSK0660, providing important controls for experimental validation.

Standard experimental protocols include:

• Cell Culture Studies: 16-hour incubation periods for tubulogenesis assays
• Animal Studies: Intravenous administration with appropriate vehicle controls
• Molecular Analysis: RT-qPCR and Western blotting for gene and protein expression
• Metabolic Assessment: Hyperinsulinemic-euglycemic clamp procedures
• Vascular Studies: HUVEC tubulogenesis and angiogenesis assays

Research emphasizes the importance of including appropriate vehicle controls (DMSO or ethanol) and following established protocols for reproducible results. Studies have shown that direct activation effects are measurable within hours of treatment, while longer-term metabolic changes may require extended treatment periods.

For vivo activation studies, research protocols must account for the compound’s pharmacokinetic properties and ensure proper solubilization for systemic administration. Laboratory guidelines recommend careful attention to handling procedures and storage conditions to maintain compound stability.

Laboratory and Statistical Analysis

The beneficial effects of GW0742 on diabetic models and body composition have been validated through a range of laboratory and statistical analysis techniques. Researchers commonly employ gene expression analysis to assess the impact of GW0742 on key metabolic pathways, particularly those involved in lipid metabolism, fatty acid oxidation, and insulin sensitivity. Mitochondrial function assays are also utilized to evaluate the compound’s influence on cellular energy production and metabolic efficiency.

Statistical analysis, including the use of ANOVA and post-hoc tests, ensures that observed differences in metabolic outcomes are robust and reproducible. Across multiple studies, these analytical approaches have consistently demonstrated that GW0742 enhances lipid metabolism, improves insulin sensitivity, and supports favorable changes in body composition in diabetic models.

The activation of pparβ δ and the resulting increase in fatty acid oxidation are central to GW0742’s metabolic effects. These findings reinforce the compound’s value as a research tool for investigating the mechanisms underlying metabolic diseases and highlight the need for continued research to fully elucidate its therapeutic potential.

Safety and Considerations

Laboratory studies have reported that GW0742 is well-tolerated in animal research models, with no significant mortality observed during standard treatment protocols. Research indicates that the compound’s effects are reversible upon treatment discontinuation, supporting its utility in controlled experimental settings.

Experimental considerations include:

• Concentration Selection: Careful selection to achieve research objectives
• Vehicle Controls: Essential for proper experimental design
• Animal Welfare: Compliance with established guidelines and ethical standards
• Storage Conditions: Appropriate handling to maintain compound integrity
• Experimental Duration: Effects are reversible after discontinuation

Research protocols emphasize the importance of proper experimental design, including appropriate control groups and statistical analysis methods. Studies suggest that the compound’s research applications require careful attention to experimental variables and standardized protocols.

Laboratory safety protocols recommend standard handling procedures for research chemicals, including appropriate personal protective equipment and waste disposal methods. Research facilities must maintain compliance with institutional guidelines for chemical handling and storage.

Future Therapeutic Potential

Research suggests considerable scientific interest in GW0742 and related peroxisome proliferator activated receptors as targets for understanding metabolic diseases. Laboratory data highlight its potential as a research tool for studying antidiabetic mechanisms, with meaningful impacts observed on insulin sensitivity, hepatic metabolism, and systemic inflammation in experimental models.

Studies indicate promising applications in metabolic syndrome and obesity research, given the global prevalence of these conditions and the need for better understanding of underlying mechanisms. Cardiovascular research suggests potential applications in studying endothelial function and hypertension prevention strategies.

Future research directions may include:

• Metabolic Disease Models: Advanced understanding of diabetes and obesity mechanisms
• Cardiovascular Research: Endothelial function and vascular biology studies
• Tissue Regeneration: Wound healing and angiogenesis mechanisms
• Mitochondrial Research: Energy metabolism and cellular function studies
• Drug Development: Understanding receptor-based therapeutic approaches

Research applications extend to studying radiation induced brain injury and other oxidative status conditions, thanks to the compound’s ability to modulate cellular stress responses. Laboratory investigations suggest potential applications in studying free radical biology and cellular protection mechanisms.

As a modulator of endothelial metabolism, GW0742 represents a valuable research tool for understanding metabolic and vascular biology. The compound’s continued use in academic and pharmaceutical research will likely inform both basic science understanding and future therapeutic innovation in the field.

Conclusion

GW0742 stands as a reference compound for PPARβ/δ research, offering researchers a powerful tool for investigating metabolic pathways, vascular biology, and disease mechanisms. Its robust research profile supports continued use in academic, translational, and pharmaceutical research settings, where it serves as both a probe for understanding nuclear receptor biology and a model for studying metabolic regulation.

Research suggests that this selective agonist will continue to inform our understanding of lipid metabolism, energy homeostasis, and cardiovascular function through carefully designed laboratory studies. As the scientific community advances our knowledge of peroxisome proliferator activated receptor pathways, GW0742 remains an essential tool for researchers committed to expanding our understanding of metabolic diseases and developing better therapeutic approaches.

For researchers interested in incorporating GW0742 into their studies, adherence to established protocols and ethical guidelines ensures both scientific rigor and responsible research practices. The compound’s continued contribution to metabolic and cardiovascular research depends on maintaining high standards of experimental design and regulatory compliance in research applications.

References

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