Uses and Mode of action of GW501516

GW501516 (also known as GW-501,516, GW1516, GSK-516, Cardarine) is a PPARδ receptor agonist that was invented in a collaboration between Ligand Pharmaceuticals and GlaxoSmithKline in the 1990s. It entered into clinical development as a drug candidate for metabolic and cardiovascular diseases, but was abandoned in 2007 because animal testing showed that the drug caused cancer to develop rapidly in several organs.

Uses

GW501516 induces a significant increase in HDL-cholesterol levels along with a reduction in TG. Elevated levels of plasma insulin are also suppressed by GW501516 treatment, whereas serum glucose levels are unaffected. These results suggest that PPAR-δ agonists may prove useful in the treatment of dyslipidemia, but it is important to note that this was a limited study with respect to species and compounds. The role of PPAR-δ in dyslipidemia requires further investigation.

Mode of action

GW501516 is a selective agonist (activator) of the PPARδ receptor.It displays high affinity (Ki = 1 nM) and potency (EC50 = 1 nM) for PPARδ with > 1,000 fold selectivity over PPARα and PPARγ.

In rats, binding of GW501516 to PPARδ recruits the coactivator PGC-1α. The PPARδ/coactivator complex in turn upregulates the expression of proteins involved in energy expenditure.Furthermore, in rats treated with GW501516, increased fatty acid metabolism in skeletal muscle and protection against diet-induced obesity and type II diabetes was observed. In obese rhesus monkeys, GW501516 increased high-density lipoprotein (HDL) and lowered very-low-density lipoprotein (VLDL).

Research

In 2007, research was published showing that high doses of GW501516 given to mice dramatically improved their physical performance; the work was widely discussed in popular media, and led to a black market for the drug candidate and to its abuse by athletes as a doping agent. The World Anti-Doping Agency (WADA) developed a test for GW501516 and other related chemicals and added them to the prohibited list in 2009; it has issued additional warnings to athletes that GW501516 is not safe.