GW1516

from Wikipedia, the free encyclopedia
Structural formula
Structure of GW501516
General
Surname GW1516
other names
  • {4 - [({4-methyl-2- [4- (trifluoromethyl) phenyl] -1,3-thiazol-5-yl} methyl) sulfanyl] 2-methylphenoxy} acetic acid ( IUPAC )
  • GW-501,516
  • GSK-516
  • Cardarine
  • Endurobol
Molecular formula C 21 H 18 F 3 NO 3 S 2
Brief description

white solid

External identifiers / databases
CAS number 317318-70-0
PubChem 9803963
ChemSpider 7979723
DrugBank DB05416
Wikidata Q5515069
properties
Molar mass 453.50 g mol −1
Physical state

firmly

safety instructions
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

GW1516 (also known under the names GW-501,516 , GW501516 , GSK-516 and on the black market as Endurobol ) is an activator ( agonist ) of the PPAR δ receptor . It was developed in a collaboration between Ligand Pharmaceuticals and GlaxoSmithKline (GSK) in the 1990s as a drug candidate for metabolic and cardiovascular diseases . Development was abandoned in 2007 after the compound caused cancer in animal studies that spread rapidly to multiple organs ( liver , stomach , tongue , skin , urinary bladder , ovaries , uterus, and testicles ).

Research published in 2007 showed that giving high doses of GW1516 to mice dramatically improved their physical performance. The work was widely discussed in popular media and resulted in a black market for the drug candidate and abuse by athletes as a doping agent . The World Anti-Doping Agency (WADA) developed a test for GW1516 and other related chemicals and added the substance to the Prohibited List in 2009; additional warnings were issued to athletes that GW1516 was not safe.

history

The effect of GW1516 was originally discovered during a research collaboration between GSK and Ligand Pharmaceuticals that began in 1992 and was published in a 2001 edition of the Proceedings of the National Academy of Sciences (PNAS) . WR Oliver et al. report that they developed the substance using “ combinatorial chemistry and structure-based drug design ”. Among the authors was a son of Leo Sternbach , who first synthesized various benzodiazepines in the 1960s .

As reported by R&D Focus Drug News , GSK began Phase I testing of the drug to treat hyperlipoproteinemia in 2000 , followed by Phase I / II testing in 2002. In 2003, Ligand Pharmaceuticals received a US $ 1 million payment as a result of GSK continued Phase I development.

In 2007, GW1516 completed two Phase II clinical studies and additional studies in obesity , diabetes , dyslipidemia, and cardiovascular disease , but GSK stopped developing the drug in 2007 for reasons not known at the time. It later emerged that administration of the drug had been discontinued because animal experiments had shown that the substance had caused cancer that quickly spread to multiple organs at doses of 3 mg per kg per day in mice and rats.

Ronald M. Evans' laboratory bought a sample of GW1516 and administered a much higher dose to mice than was used in GSK's experiments. The compound was found to dramatically increase the physical performance of the mice. The work was published in Cell in 2007 , which received widespread coverage in the popular science press including the New York Times and the Wall Street Journal .

Use for doping

Prior to the 2008 Summer Olympics in Beijing , scientists expressed concern that GW1516 could be used by athletes to improve athletic performance , as it was not restricted by regulations at the time, nor could it be detected by standard tests. In collaboration with the World Anti-Doping Agency (WADA), researchers developed a doping test for GW1516 and another PPAR modulator. In 2009, WADA added these substances to the prohibited list.

GW1516 was advertised on bodybuilding and athletics websites, and as of 2011 it had been available on the black market for some time . In 2011, 10 g of the substance cost 1,000 US dollars. In 2012, WADA categorized GW1516 from a gene doping compound to a “hormone and metabolism modulator”.

In 2013, WADA took the rare step of warning potential users of the substance about the possible health risks, in which it informed them that serious side effects had been observed and that there was no clinical approval for this substance and there would not be any; the New Scientist attributed this warning to the compound's cancer risk.

A number of athletes have tested positive for GW1516. At the Vuelta Ciclista a Costa Rica in December 2012, four Costa Rican cyclists tested positive for GW1516. In the following years, other athletes from cycling and racing also had positive doping tests.

In 2017, the media - including German - reported again on various occasions about GW1516, without mentioning the known cancer risk and doping offenders who had already been caught. These reports should appear on a corresponding article on EurekAlert! go back.

Mode of action

GW1516 is a selective agonist (activator) of the PPARδ receptor. It shows a high affinity (K i = 1 nM) and potency (EC 50 = 1 nM) for PPARδ with more than 1000-fold selectivity compared to PPARα and PPARγ.

In rats, the binding of GW1516 to the PPAR recruited coactivator PGC-1α ( P eroxisome proliferator-activated receptor g amma c oactivator 1 - alpha , PPARGC1A). The PPARδ / coactivator complex in turn upregulates the expression of proteins that are involved in energy consumption. In addition, increased fatty acid metabolism in skeletal muscle and protection against diet-induced obesity and type 2 diabetes were observed in rats treated with GW1516 . In obese rhesus monkeys, GW1516 increased the high density lipoprotein (HDL) and decreased the very low density lipoprotein (VLDL). It is assumed that - triggered by GW1516 - type I muscle fibers ("endurance muscles") are increasingly formed, as are enzymes for lipolysis . Both of these make the substance an effective doping agent.

See also

Web links

Individual evidence

  1. ↑ a b c d data sheet GW501516, ≥98% (HPLC) from Sigma-Aldrich , accessed on September 25, 2017 ( PDF ).
  2. ↑ a b Anti-doping agency warns cheats on the health risks of Endurobol. In: The Conversation. March 22, 2013, accessed March 28, 2020 .
  3. ↑ A. Sahebkar, GT Chew, GF Watts: New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease . In: Expert Opin Pharmacother . tape 15 , no. 4 , 2014, p. 493-503 , doi : 10.1517 / 14656566.2014.876992 , PMID 24428677 (English). "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) ".
  4. ↑ GW501516 GlaxoSmithKline, Ligand milestone payment . In: R&D Focus Drug News . June 28, 2004.
  5. ^ G. Wolf: The function of the nuclear receptor peroxisome proliferator-activated receptor delta in energy homeostasis . In: Nutr. Rev. Band 61 , no. 11 , November 2003, p. 387-390 , doi : 10.1301 / no . 2003.nov.387-390 , PMID 14677574 .
  6. ↑ a b W. R. Oliver, JL Shenk, MR Snaith, CS Russell, KD Plunket, NL Bodkin, MC Lewis, DA Winegar, ML Sznaidman, MH Lambert, HE Xu, DD Sternbach, SA Kliewer, BC Hansen, TM Willson: A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport . In: Proc. Natl. Acad. Sci. USA band 98 , no. 9 , April 2001, p. 5306–5311 , doi : 10.1073 / pnas.091021198 , PMID 11309497 , PMC 33205 (free full text).
  7. ↑ Julia Flynn: Father and Son: In Two Generations, Drug Research Sees a Big Shift. (No longer available online.) In: The Wall Street Journal. February 11, 2004, formerly in the original ; accessed in 2004 .  ( Page no longer available , search in web archives )@1@ 2Template: Dead Link / www.wsj.com
  8. ↑ GW501516 Glaxo Wellcome phase change I, UK . In: R&D Focus Drug News . November 20, 2000.
  9. ↑ GW501516 GlaxoSmithKline phase change II, UK . In: R&D Focus Drug News . February 25, 2002.
  10. ↑ Ligand Pharmaceuticals Incorporated Earns $ 1 Million Milestone Payment as GlaxoSmithKline Advances Development of 501516. Reuters Significant Developments, June 5, 2003, accessed March 28, 2020 .
  11. ↑ GD Barish, VA Narkar, RM Evans: PPAR delta: a dagger in the heart of the metabolic syndrome . In: J. Clin. Invest. tape 116 , no. 3 , March 2006, p. 590–597 , doi : 10.1172 / JCI27955 , PMID 16511591 , PMC 1386117 (free full text).
  12. ↑ Uwe Dressel, Tamara L. Allen, Jyotsna B. Pippal, Paul R. Rohde, Patrick Lau, George EO Musc: 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 . In: Molecular Endocrinology . tape 17 , no. 12 , 2003, p. 2477-2493 , doi : 10.1210 / me.2003-0151 , PMID 14525954 .
  13. ↑ AN Billin: PPAR-beta / delta agonists for Type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home . In: Expert Opin Investig Drugs . tape 17 , no. 10 , October 2008, p. 1465-1471 , doi : 10.1517 / 13543784.17.10.1465 , PMID 18808307 .
  14. ↑ A. Sahebkar, GT Chew, GF Watts: New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease . In: Expert Opin Pharmacother . tape 15 , no. 4 , 2014, p. 493–503 , doi : 10.1517 / 14656566.2014.876992 , PMID 24428677 : “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) "
  15. ^ LE Geiger, WS Dunsford, DJ Lewis, C. Brennan, KC Liu, SJ Newsholme: PS 895 - Rat carcinogenicity study with GW501516, a PPAR delta agonist . In: 48th Annual Meeting of the Society of Toxicology . Society of Toxicology .
  16. ^ SJ Newsholme, WS Dunsford, T. Brodie, C. Brennan, M. Brown, LE Geiger: PS 896 - Mouse carcinogenicity study with GW501516, a PPAR delta agonist. . In: 48th Annual Meeting of the Society of Toxicology . Society of Toxicology.
  17. ↑ a b Michael Bezar: Faster. Higher. Squeakier. In: Outside magazine. November 1, 2011, accessed April 2, 2013 .
  18. ^ J. Laurance, A. Rajan: Health News, Health & Wellbeing - Warning to Beijing Olympics over pills that mimic exercise. In: The Independent. August 1, 2008, accessed August 1, 2008 .
  19. ^ Prohibited List. (PDF) (No longer available online.) WADA, 2009, archived from the original on February 3, 2009 ; accessed on March 28, 2020 .
  20. ^ A b Anti-doping agency warns athletes of black market drug. In: New Scientist. March 26, 2013, accessed March 28, 2020 .
  21. ^ M. Thevis, H. Geyer, A. Thomas, W. Schänzer: 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 . In: Drug Test Anal . tape 3 , no. 5 , May 2011, p. 331-336 , doi : 10.1002 / dta.283 , PMID 21538997 .
  22. ^ F. Sanchis-Gomar, G. Lippi: Telmisartan as metabolic modulator: a new perspective in sports doping? In: J Strength Cond Res . tape 26 , no. 3 , March 2012, p. 608-610 , doi : 10.1519 / JSC.0b013e31824301b6 , PMID 22130396 .
  23. ^ WADA issues alert on GW501516. (No longer available online.) World Anti-Doping Agency, March 21, 2013, archived from the original on June 2, 2013 ; accessed on March 28, 2020 .
  24. ↑ Shane Stokes: GW501516 positive confirmed, three of four riders are from the same BCR Pizza Hut team , on: velonation.com. April 15, 2013.
  25. ↑ Shane Stokes: Four riders each handed two year bans for use of GW501516. on: velonation.com , July 30, 2013.
  26. ^ List of sanctions. (No longer available online.) Uci.ch, August 1, 2008, archived from the original on July 15, 2014 ; accessed on March 28, 2020 .
  27. ↑ European champion Valery Kaykov sacked for failing drug test. In: BBC. April 11, 2013, accessed April 11, 2013 .
  28. ↑ Gregory Blachier: Venezuelan Ubeto tests positive for high-risk drug. In: Reuters Sports News. May 5, 2013, accessed April 19, 2018 .
  29. ^ Sanctioned athletes list, June 26, 2014
  30. ↑ Associated Press: Doping probe launched into Russian walkers , on: espn.com. July 11, 2014.
  31. ↑ Is the "fitness pill" coming? , on: scinexx from May 5, 2017.
  32. ↑ Daniela Zeibig: Sports pill keeps mice fit. on: Spektrum.de , May 2, 2017.
  33. ↑ Salk Institute: 'Exercise-in-a-pill' boosts athletic endurance by 70 percent , aif: EurekAlert of May 2, 2017.
  34. ↑ P. Pelton: GW501516 GlaxoSmithKline / Ligand . In: Curr Opin Investig Drugs . tape 7 , no. 4 , April 2006, p. 360-370 , PMID 16625823 .
  35. ↑ a b D. L. Speaker: Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta . In: Am. J. Cardiol. tape 100 , 11, Suppl. 1, December 2007, pp. 20–24 , doi : 10.1016 / j.amjcard.2007.08.009 , PMID 18047848 .
  36. ↑ Doping: Bought Performance - How doping substances should work. In: Deutsche Apotheker Zeitung. No. 7, 2014, Section S4: Hormones and metabolic modulators, PPARδ and AMPK agonists