GW501516

History

GW501516 was initially discovered during a research collaboration between GSK and Ligand Pharmaceuticals that began in 1992. 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.

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. In 2003, Ligand Pharmaceuticals earned a $1 million payment as a result of GSK continuing phase I development.

By 2007, GW501516 had completed two phase II clinical studies and other studies relating to obesity, diabetes, dyslipidemia, and cardiovascular disease, but GSK abandoned further development of the drug in 2007 for reasons which were not disclosed at the time. It later emerged that the drug was discontinued because animal testing showed that the drug caused cancer to develop rapidly in several organs, at dosages of 3 mg/kg/day in both mice and rats.

Ronald M. Evans's laboratory purchased a sample of GW501516 and gave mice a much higher dose than had been used in GSK's experiments; they found that the compound dramatically increased the physical performance of the mice. The work was published in 2007 in Cell and was widely reported in the popular press including The New York Times and The Wall Street Journal.

Another human study (comparing cardarine with the PPARα agonist GW590735 and placebo) was published in 2021.

Performance-enhancing drug

Concerns were raised prior to the 2008 Beijing Olympics that GW501516 could be used by athletes as a 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) developed a test for GW501516 and other related PPARδ modulators, and added such drugs to the prohibited list in 2009.

GW501516 has been promoted on bodybuilding and athletics websites and by 2011 had already been available for some time on the black market. In 2011, it was reported to cost $1,000 for 10 g.

In 2013, WADA took the rare step of warning potential users of the compound of the possible health risks, stating that "clinical approval has not, and will not be given for this substance"; the New Scientist attributed the warning to the risks of the drug causing cancer.

A number of athletes have tested positive for GW501516. At the Vuelta Ciclista a Costa Rica in December 2012, four Costa Rican riders tested positive for GW501516. Three of them received two-year suspensions, while the fourth received 12 years as it was his second doping violation. In April 2013, Russian cyclist Valery Kaykov was suspended by cycling's governing body UCI after having tested positive for GW501516. Kaykov's team RusVelo dismissed him immediately and in May 2013, Venezuelan Miguel Ubeto was provisionally suspended by the Lampre team. In February 2014, Russian race walker Elena Lashmanova tested positive for GW501516. In April 2019, American heavyweight boxer Jarrell Miller tested positive for GW501516 which caused his challenge for Anthony Joshua's World Heavyweight titles to be cancelled. In December 2020, Miller was suspended for 2 years for repeated violations. In July 2022, the 2012 800m Olympic silver medalist from Botswana, Nijel Amos tested positive for GW501516 and was provisionally suspended just days before the 2022 World Athletics Championships. Surinam's Issam Asinga, who set the under-20 world track record in the men's 100 meters, was informed on Aug. 9, 2023 by the Athletics Integrity Unit that his July 18 drug test the prior month detected trace amounts of GW501516. Asinga has alleged in a suit filed in the Southern District of New York that Gatorade provided him with Gatorade Recovery Gummies at their awards ceremony one week earlier in Los Angeles tainted with GW501516.

Mechanism of action

GW501516 is a selective agonist of the PPARδ receptor. It displays high affinity (Ki = 1 nM) and potency (EC50 = 1 nM) for PPARδ with greater than 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).

Activation of PPARδ is also believed to be the mechanism responsible for cancer induction. A 2018 study in finds that GW501516 enhances the growth of colitis-associated colorectal cancer by increasing inflammation and the expression of GLUT1 and SLC1A5.

References

References

1. (2013-03-22). "Anti-doping agency warns cheats on the health risks of Endurobol". The Conversation.
2. (28 June 2004). "GW501516 GlaxoSmithKline, Ligand milestone payment.". R & D Focus Drug News.
3. (November 2003). "The function of the nuclear receptor peroxisome proliferator-activated receptor delta in energy homeostasis". Nutr. Rev..
4. (April 2001). "A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport". Proc. Natl. Acad. Sci. U.S.A..
5. (11 February 2004}}{{Dead link). "Father and Son: In Two Generations, Drug Research Sees a Big Shift". The Wall Street Journal.
6. (20 November 2000). "GW501516 Glaxo Wellcome phase change I, UK". R & D Focus Drug News.
7. (25 February 2002). "GW501516 GlaxoSmithKline phase change II, UK". R & D Focus Drug News.
8. (5 June 2003). "Ligand Pharmaceuticals Incorporated Earns $1 Million Milestone Payment as GlaxoSmithKline Advances Development of 501516". Reuters Significant Developments.
9. (March 2006). "PPAR delta: a dagger in the heart of the metabolic syndrome". The Journal of Clinical Investigation.
10. (December 2003). "The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells". Molecular Endocrinology.
11. (October 2008). "PPAR-beta/delta agonists for Type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home". Expert Opinion on Investigational Drugs.
12. (March 2014). "New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease". Expert Opinion on Pharmacotherapy.
13. (2009). "PS 895 - Rat carcinogenicity study with GW501516, a PPAR delta agonist". [[Society of Toxicology]].
14. (2009). "PS 896 - Mouse carcinogenicity study with GW501516, a PPAR delta agonist.". [[Society of Toxicology]].
15. (May 2017). "PPARδ Promotes Running Endurance by Preserving Glucose". Cell Metabolism.
16. (2011-11-01). "Faster. Higher. Squeakier.". Outside magazine.
17. (30 July 2021). "Cardarine (GW501516) Effects on Improving Metabolic Syndrome". Journal of Health, Sports, and Kinesiology.
18. (2008-08-01). "Warning to Beijing Olympics over pills that mimic exercise". The Independent.
19. [http://www.wada-ama.org/rtecontent/document/2009_Prohibited_List_ENG_Final_20_Sept_08.pdf WADA 2009 Prohibited List] {{webarchive. link. (February 3, 2009)
20. (2013-03-26). "Anti-doping agency warns athletes of black market drug". New Scientist.
21. (May 2011). "Trafficking of drug candidates relevant for sports drug testing: detection of non-approved therapeutics categorized as anabolic and gene doping agents in products distributed via the Internet". Drug Test Anal.
22. (March 2012). "Telmisartan as metabolic modulator: a new perspective in sports doping?". J Strength Cond Res.
23. (2013-03-21). "WADA issues alert on GW501516". World Anti-Doping Agency.
24. (15 April 2013). "GW501516 positives confirmed, three of four riders are from same BCR Pizza Hut team". velonation.com.
25. (30 July 2013). "Four riders each handed two year bans for use of GW501516". velonation.com.
26. link. (July 15, 2014 , uci.ch)
27. (2013-04-11). "European champion Valery Kaykov sacked for failing drug test". BBC.
28. (2013-05-13). "Miguel Ubeto Aponte provisionally suspended". UCI.
29. [http://www.iaaf.org/download/download?filename=64099fcf-1e9a-444d-97d9-ea03d79fd4c5.pdf&urlslug=List%20of%20athletes%20currently%20serving%20a%20period%20of%20ineligibility%20as%20a%20result%20of%20an%20Anti-Doping%20Rule%20Violation%20under%20IAAF%20Rules Sanctioned athletes list – 26 June 2014]
30. Associated Press: [https://www.espn.com/espn/wire?section=trackandfield&id=11201932 Doping probe launched into Russian walkers], espn.com, 11 July 2014
31. (2019-04-19). "Sources: 'Big Baby' Miller failed three drug tests". [[ESPN.com]].
32. (2 December 2020). "Heavyweight Miller gets 2-year PED suspension". ESPN.com.
33. (13 July 2022). "London 2012 medallist Nijel Amos suspended after positive doping test". the Guardian.
34. (11 July 2022). "Teen sprinter sues Gatorade over doping ban that cost him an Olympic spot". The Washington Post.
35. (April 2006). "GW-501516 GlaxoSmithKline/Ligand". Current Opinion in Investigational Drugs.
36. (December 2007). "Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta". The American Journal of Cardiology.
37. (January 2019). "PPARδ agonist enhances colitis-associated colorectal cancer". European Journal of Pharmacology.