GW501516

GW501516 (also known as GW-501,516, GW1516, GSK-516 and Endurobol ) is a PPARδ receptor agonist that was previously investigated for drug use by GlaxoSmithKline. The drug was discovered to cause cancer in rats and GlaxoSmithKline has ceased development. It activates the same pathways activated through exercise, including PPARδ and AMP-activated protein kinase. It had been investigated as a potential treatment for obesity, diabetes, dyslipidemia and cardiovascular disease. GW501516 has a synergistic effect when combined with AICAR: the combination has been shown to significantly increase exercise endurance in animal studies more than either compound alone.

History
GW501516 was initially discovered during a research collaboration between GSK and Ligand Pharmaceuticals that began in 1992. R & D Focus Drug News reported that GSK began phase I trials of the compound for the treatment of hyperlipidemia in 2000 followed by phase I/II in 2002. The discovery of the compound was published in a 2001 issue of PNAS. Oliver et al. reported that they used "combinatorial chemistry and structure-based drug design" to develop it. One of the authors was the son of Leo Sternbach who discovered benzodiazepines in the 1960s. In 2003, Ligand Pharmaceuticals earned a $1 million payment as a result of GSK continuing phase I development.

GW501516 had completed two phase II clinical studies but GSK abandoned further development of the drug in 2007 for reasons which where not disclosed as of 2008.

Ronald M. Evans from the Salk Institute wishes to create the "first-ever performance-enhancing drug that can radically boost physical endurance in humans". In 2004 he had showed that mice genetically engineered to express PPARδ in muscle cells had greater endurance. He called the mice "marathon mice". He purchased a sample of GW501516 and gave mice a much higher dose than had been in research by GSK and found that the compound increased the endurance of the mice. The research culminated in a 2007 paper in Cell that was widely reported in the popular press including The New York Times and The Wall Street Journal.

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 > 1000 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). The mechanism by which PPARδ agonists increase HDL appears to be a result of increased expression of the cholesterol transporter ABCA1.

Use in doping in sports
In a 2004 article in New Scientist Ronald M. Evans stated "I suspect that animals training with the drug will increase endurance more rapidly," and that "the potential for this to be abused by athletes is real." A spokeswoman for WADA said it would not be surprising if athletes were to take the substance if it was available. GSK told New Scientist that it had not investigated whether the compound had any effect on endurance.

Concerns were raised prior to the 2008 Beijing Olympics that GW501516 could be used by athletes as an ergogenic performance enhancing drug that was not currently controlled by regulations or detected by standard tests. One of the main researchers from the study on enhanced endurance consequently developed a urine test to detect the drug, and made it available to the International Olympic Committee. The World Anti-Doping Agency (WADA) has also begun work on a test for GW501516 and other related PPARδ modulators, and they have been added to the prohibited list from 2009 onwards. GW501516 has been promoted on bodybuilding and athletics websites and has been available for some time on the grey market. In 2011 it was reported to cost $1000 for 10 g. WADA claim to have already detected its use. In 2012, WADA recategorised GW501516 from a gene doping compound to a "hormone and metabolic modulator".

In April 2013, Russian cyclicst Valery Kaykov was suspended by cycling's governing body UCI after having tested positive for GW501516. Kaykov's team Rusvelo sacked him immediately and in May 2013, Venezuelan Miguel Ubeto was provisionally suspended by the Lampre team.

Safety
A 2004 article in The Wall Street Journal noted that a study published in Nature Medicine had found that GW501516 increased polyps in specially-bred mice, but GSK said that they had not identified any safety problems with the compound and would continue to develop it.

In 2013 New Scientist reported that "tests on rats showed that at all doses, the drug rapidly causes cancers in a multitude of organs, including the liver, bladder, stomach, skin, thyroid, tongue, testes, ovaries and womb." In 2013 WADA took the rare step of warning potential users of the compound of the possible health risks. They stated "clinical approval has not, and will not be given for this substance".