GW-4064

GW-4064 is a synthetic, non-steroidal compound that acts as a potent and selective agonist of the farnesoid X receptor (FXR), a nuclear receptor that plays a critical role in the regulation of bile acid, lipid, and glucose metabolism. This compound has been extensively studied for its potential therapeutic applications in metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), cholestasis, and atherosclerosis.

Chemical Structure and Properties

GW-4064 is characterized by its unique chemical structure, which allows it to bind with high affinity to the FXR. The molecular formula of GW-4064 is C28H30N2O3S, and it has a molecular weight of 474.62 g/mol. The compound is typically synthesized through a series of chemical reactions involving the formation of a thiazole ring, which is crucial for its activity as an FXR agonist.

Mechanism of Action

As an FXR agonist, GW-4064 binds to the FXR receptor, which is primarily expressed in the liver, intestine, kidney, and adrenal glands. Upon activation, FXR regulates the expression of genes involved in bile acid synthesis, transport, and metabolism. This includes the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis, and the induction of bile salt export pump (BSEP), which facilitates the excretion of bile acids from the liver.

Therapeutic Applications

Non-Alcoholic Fatty Liver Disease (NAFLD)

GW-4064 has shown promise in the treatment of NAFLD by reducing liver fat accumulation and inflammation. FXR activation by GW-4064 leads to improved lipid metabolism and insulin sensitivity, which are beneficial in managing NAFLD.

Cholestasis

In cholestasis, the flow of bile from the liver is impaired. GW-4064, through FXR activation, enhances the expression of transporters that facilitate bile acid excretion, thereby alleviating cholestatic conditions.

Atherosclerosis

GW-4064 has been investigated for its potential to reduce atherosclerosis by modulating lipid metabolism and reducing inflammation. FXR activation can lead to decreased levels of circulating triglycerides and cholesterol, which are risk factors for atherosclerosis.

Research and Development

GW-4064 has been a valuable tool in research to understand the role of FXR in metabolic diseases. While it has not been developed into a therapeutic drug for clinical use, its analogs and derivatives continue to be explored for potential clinical applications.

Safety and Side Effects

The safety profile of GW-4064 has been primarily evaluated in preclinical studies. Common side effects observed in animal models include alterations in liver enzyme levels and changes in lipid profiles. Further studies are needed to fully understand its safety in humans.

Also see

• Farnesoid X receptor
• Bile acid
• Non-alcoholic fatty liver disease
• Cholestasis
• Atherosclerosis