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| Other names | GW-501,516, GW1516, GSK-516, cardarine, endurobol |
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| Routes of administration | By mouth |
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| Formula | C21H18F3NO3S2 |
| Molar mass | 453.49 g·mol−1 |
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GW501516 (also known asGW-501,516,GW1516,GSK-516,cardarine, and on theblack market asendurobol[1]) is aPPARδreceptor agonist that was invented in a collaboration betweenLigand Pharmaceuticals andGlaxoSmithKline in the 1990s. It entered into clinical development as a drug candidate formetabolic andcardiovascular diseases, but was abandoned in 2007 becauseanimal testing showed that the drug caused cancer to develop rapidly in several organs.[2]
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 adoping agent. TheWorld 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.
GW501516 was initially discovered during a research collaboration betweenGSK andLigand Pharmaceuticals that began in 1992.[3] The discovery of the compound was published in a 2001 issue ofPNAS.[4] Oliveret al. reported that they used "combinatorial chemistry andstructure-based drug design" to develop it.[5] One of the authors was the son ofLeo Sternbach who discoveredbenzodiazepines in the 1960s.[6]
R & D Focus Drug News reported that GSK beganphase I trials of the compound for the treatment ofhyperlipidemia in 2000[7] followed by phase I/II in 2002.[8] In 2003, Ligand Pharmaceuticals earned a $1 million payment as a result of GSK continuing phase I development.[9]
By 2007, GW501516 had completed two phase II clinical studies and other studies relating toobesity,diabetes,dyslipidemia, andcardiovascular disease,[10][11] but GSK abandoned further development of the drug in 2007 for reasons which were not disclosed at the time.[12] It later emerged that the drug was discontinued becauseanimal 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.[2][13][14]
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.[15] The work was published in 2007 inCell and was widely reported in the popular press includingThe New York Times andThe Wall Street Journal.[16]
Another human study (comparing cardarine with the PPARα agonistGW590735 and placebo) was published in 2021.[17]
Concerns were raised prior to the2008 Beijing Olympics that GW501516 could be used by athletes as aperformance-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 theInternational Olympic Committee. TheWorld Anti-Doping Agency (WADA) developed a test for GW501516 and other relatedPPARδ modulators,[18] and added such drugs to the prohibited list in 2009.[19]
GW501516 has been promoted onbodybuilding and athletics websites[20] and by 2011 had already been available for some time on theblack market.[1][21] In 2011, it was reported to cost $1,000 for 10 g.[16] In 2012, WADA recategorised GW501516 from agene doping compound to a "hormone and metabolic modulator".[22]
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"; theNew Scientist attributed the warning to the risks of the drug causing cancer.[20][23]
A number of athletes have tested positive for GW501516. At theVuelta 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.[24][25][26] In April 2013, Russian cyclistValery Kaykov was suspended by cycling's governing bodyUCI after having tested positive for GW501516. Kaykov's teamRusVelo dismissed him immediately[27] and in May 2013, VenezuelanMiguel Ubeto was provisionally suspended by the Lampre team.[28] In February 2014, Russian race walkerElena Lashmanova tested positive for GW501516.[29][30] In April 2019, American heavyweight boxerJarrell Miller tested positive for GW501516 which caused his challenge forAnthony Joshua's World Heavyweight titles to be cancelled.[31] In December 2020, Miller was suspended for 2 years for repeated violations.[32] In July 2022, the 2012 800 m Olympic silver medalist from Botswana,Nijel Amos tested positive for GW501516 and was provisionally suspended just days before the2022 World Athletics Championships.[33] Surinam'sIssam Asinga, who set the under-20 world track record in the men's 100 meters, was informed on Aug. 9, 2023 by theAthletics 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 thatGatorade provided him with Gatorade Recovery Gummies at their awards ceremony one week earlier in Los Angeles tainted with GW501516.[34]
GW501516 is a selectiveagonist of thePPARδ receptor.[35] It displays high affinity (Ki = 1 nM) and potency (EC50 = 1 nM) for PPARδ with greater than1,000-fold selectivity overPPARα andPPARγ.[5]
In rats, binding of GW501516 to PPARδ recruits thecoactivatorPGC-1α. The PPARδ/coactivator complex in turn upregulates the expression of proteins involved in energy expenditure.[36] Furthermore, in rats treated with GW501516, increased fatty acid metabolism in skeletal muscle and protection against diet-induced obesity andtype II diabetes was observed. In obese rhesus monkeys, GW501516 increasedhigh-density lipoprotein (HDL) and loweredvery-low-density lipoprotein (VLDL).[36]
Activation of PPARδ is also believed to be the mechanism responsible for cancer induction. A 2018 study found that GW501516 enhanced the growth ofcolitis-associatedcolorectal cancer in mice by increasing inflammation and the expression ofGLUT1 andSLC1A5.[37]
Despite these promising early results, the further investigation and development of GW501516 was discontinued after observations in animal studies of its association with the rapid induction of cancers in several organs (liver, stomach, tongue, skin, bladder, ovaries, womb and testes
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