GW501516

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GW501516
Gw501516.svg
Systematic (IUPAC) name
{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid[1]
Clinical data
Trade names Endurobol
Pregnancy cat. N/A
Legal status Unscheduled (AU) unscheduled (UK) unscheduled (US)
Routes oral
Identifiers
CAS number 317318-70-0 N
ATC code None
PubChem CID 9803963
IUPHAR ligand 2687
ChemSpider 7979723
ChEBI CHEBI:73726 YesY
ChEMBL CHEMBL38943 N
Chemical data
Formula C21H18F3NO3S2 
Mol. mass 453.498 g/mol
 N (what is this?)  (verify)

GW501516 (also known as GW-501,516, GW1516, GSK-516 and Endurobol[2]) 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.[3][4] 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.[5][6] 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.[7][8]

History[edit]

GW501516 was initially discovered during a research collaboration between GSK and Ligand Pharmaceuticals that began in 1992.[9] R & D Focus Drug News reported that GSK began phase I trials of the compound for the treatment of hyperlipidemia in 2000[10] followed by phase I/II in 2002.[11] The discovery of the compound was published in a 2001 issue of PNAS.[12] Oliver et al. reported that they used "combinatorial chemistry and structure-based drug design" to develop it.[13] One of the authors was the son of Leo Sternbach who discovered benzodiazepines in the 1960s.[14] In 2003, Ligand Pharmaceuticals earned a $1 million payment as a result of GSK continuing phase I development.[15]

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.[16]

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".[17][18] 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.[17]

Mode of action[edit]

GW501516 is a selective agonist (activator) of the PPARδ receptor.[19] It displays high affinity (Ki = 1 nM) and potency (EC50 = 1 nM) for PPARδ with > 1000 fold selectivity over PPARα and PPARγ.[13]

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.[20] 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).[20] The mechanism by which PPARδ agonists increase HDL appears to be a result of increased expression of the cholesterol transporter ABCA1.[5]

Use in doping in sports[edit]

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.[18]

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,[21] and they have been added to the prohibited list from 2009 onwards.[22] GW501516 has been promoted on bodybuilding and athletics websites[4] and has been available for some time on the grey market.[2][23] In 2011 it was reported to cost $1000 for 10 g.[17] WADA claim to have already detected its use.[24] In 2012, WADA recategorised GW501516 from a gene doping compound to a "hormone and metabolic modulator".[25]

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 got 12 years as it was his second doping violation.[26][27][28] 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[29] and in May 2013, Venezuelan Miguel Ubeto was provisionally suspended by the Lampre team.[30]

Safety[edit]

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,[3][31] but GSK said that they had not identified any safety problems with the compound and would continue to develop it.[14] Researchers from GSK presented findings of the effects of giving GW501516 to rats and mice for two years at the 2009 meeting of the Society of Toxicology. The compound was found to significantly increase the chances of developing cancer and development of the drug was subsequently halted.[32][33][34]

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."[4] 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".[2][24]

See also[edit]

References[edit]

  1. ^ Donald J. Voet; Judith G. Voet (2011). "Energy Metabolism: Integration and Organ Specialization". Biochemistry, Fourth edition. Wiley. p. 1106. ISBN 978-0470-91745-9. 
  2. ^ a b c "Anti-doping agency warns cheats on the health risks of Endurobol". The Conversation. 2013-03-22. 
  3. ^ a b Gupta RA, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN (March 2004). "Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth". Nat. Med. 10 (3): 245–7. doi:10.1038/nm993. PMID 14758356. 
  4. ^ a b c "Anti-doping agency warns athletes of black market drug". New Scientist. 2013-03-26. 
  5. ^ a b Barish GD, Narkar VA, Evans RM (March 2006). "PPAR delta: a dagger in the heart of the metabolic syndrome". J. Clin. Invest. 116 (3): 590–7. doi:10.1172/JCI27955. PMC 1386117. PMID 16511591. 
  6. ^ Uwe Dressel, Tamara L. Allen, Jyotsna B. Pippal, Paul R. Rohde, Patrick Lau, and George E. O. Musc (2003). "The Peroxisome Proliferator-Activated Receptor β/δ Agonist, GW501516, Regulates the Expression of Genes Involved in Lipid Catabolism and Energy Uncoupling in Skeletal Muscle Cells". Molecular Endocrinology 17 (12): 2477–93. doi:10.1210/me.2003-0151. PMID 14525954. 
  7. ^ Narkar VA, Downes M, Yu RT, Embler E, Wang Y-X, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM (August 2008). "AMPK and PPARδ Agonists Are Exercise Mimetics" (PDF). Cell 134 (3): 1–11. doi:10.1016/j.cell.2008.06.051. PMC 2706130. PMID 18674809. 
  8. ^ "Exercise In A Pill: Researchers Identify Drugs That Enhance Exercise Endurance". Science News. ScienceDaily. 2008-08-01. Retrieved 2008-08-01. 
  9. ^ "GW501516 GlaxoSmithKline, Ligand milestone payment.". R & D Focus Drug News. 28 June 2004. 
  10. ^ "GW501516 Glaxo Wellcome phase change I, UK". R & D Focus Drug News. 20 November 2000. 
  11. ^ "GW501516 GlaxoSmithKline phase change II, UK". R & D Focus Drug News. 25 February 2002. 
  12. ^ Wolf G (November 2003). "The function of the nuclear receptor peroxisome proliferator-activated receptor delta in energy homeostasis". Nutr. Rev. 61 (11): 387–90. doi:10.1301/nr.2003.nov.387-390. PMID 14677574. 
  13. ^ a b Oliver WR, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM (April 2001). "A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport". Proc. Natl. Acad. Sci. U.S.A. 98 (9): 5306–11. doi:10.1073/pnas.091021198. PMC 33205. PMID 11309497. 
  14. ^ a b Julia Flynn (11 February 2004). "Father and Son: In Two Generations, Drug Research Sees a Big Shift". The Wall Street Journal. 
  15. ^ "Ligand Pharmaceuticals Incorporated Earns $1 Million Milestone Payment as GlaxoSmithKline Advances Development of 501516". Reuters Significant Developments. 5 June 2003. 
  16. ^ Billin AN (October 2008). "PPAR-beta/delta agonists for Type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home". Expert Opin Investig Drugs 17 (10): 1465–71. doi:10.1517/13543784.17.10.1465. PMID 18808307. 
  17. ^ a b c Michael Bezar (2011-11-01). "Faster. Higher. Squeakier.". Outside magazine. Retrieved 2013-04-02. 
  18. ^ a b Philip Cohen (28 August 2004). "Marathon mice can run and run". New Scientist. 
  19. ^ Pelton P (April 2006). "GW501516 GlaxoSmithKline/Ligand". Curr Opin Investig Drugs 7 (4): 360–70. PMID 16625823. 
  20. ^ a b Sprecher DL (December 2007). "Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta". Am. J. Cardiol. 100 (11 A): n20–4. doi:10.1016/j.amjcard.2007.08.009. PMID 18047848. 
  21. ^ Laurance J, Rajan A (2008-08-01). "Warning to Beijing Olympics over pills that mimic exercise". Health News, Health & Wellbeing. The Independent. Retrieved 2008-08-01. 
  22. ^ WADA 2009 Prohibited List
  23. ^ Thevis M, Geyer H, Thomas A, Schänzer W (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 3 (5): 331–6. doi:10.1002/dta.283. PMID 21538997. 
  24. ^ a b "WADA issues alert on GW501516". World Anti-Doping Agency. 2013-03-21. 
  25. ^ Sanchis-Gomar F, Lippi G (March 2012). "Telmisartan as metabolic modulator: a new perspective in sports doping?". J Strength Cond Res 26 (3): 608–10. doi:10.1519/JSC.0b013e31824301b6. PMID 22130396. 
  26. ^ Shane Stokes: GW501516 positives confirmed, three of four riders are from same BCR Pizza Hut team, velonation.com, 15 April 2013
  27. ^ Shane Stokes: Four riders each handed two year bans for use of GW501516, velonation.com 30 July 2013
  28. ^ List of sanctions, uci.ch
  29. ^ "European champion Valery Kaykov sacked for failing drug test". BBC. 2013-04-11. Retrieved 2013-04-11. 
  30. ^ "Miguel Ubeto Aponte provisionally suspended". UCI. 2013-05-13. Retrieved 2013-05-15. 
  31. ^ Tachibana K, Yamasaki D, Ishimoto K, Doi T (2008). "The Role of PPARs in Cancer". PPAR Res 2008: 102737. doi:10.1155/2008/102737. PMC 2435221. PMID 18584037. 
  32. ^ Chris Cooper (23 February 2014). "GW501516, Endurobol and doping: what’s all the fuss about?". 
  33. ^ L. E. Geiger, W. S. Dunsford, D. J. Lewis, C. Brennan, K. C. Liu and S. J. Newsholme (2009). "895 - Rat carcinogenicity study with GW501516, a PPAR delta agonist". Society of Toxicology. 
  34. ^ S. J. Newsholme, W. S. Dunsford, T. Brodie, C. Brennan, M. Brown and L. E. Geiger (2009). "896 - Mouse carcinogenicity study with GW501516, a PPAR delta agonist.". Society of Toxicology.