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Revision as of 16:30, 2 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,049 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL', 'CAS_number').← Previous edit Latest revision as of 21:16, 7 December 2024 edit undoBoghog (talk | contribs)Autopatrolled, Extended confirmed users, IP block exemptions, New page reviewers, Pending changes reviewers, Rollbackers, Template editors137,879 edits consistent citation formatting 
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{{Short description|Abandoned metabolic and cardiovascular drug}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox {{Drugbox
| Watchedfields = changed | Verifiedfields = changed
| verifiedrevid = 403603665 | verifiedrevid = 458657924
| IUPAC_name = 2-[2-methyl-4-([4-methyl-2-[4-(trifluoromethyl)phenyl)- | IUPAC_name = {2-methyl-4--1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid
| image = GW501516.png | image = GW501,516.svg
| width = 260 | width = 270


<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename =
| legal_AU = unscheduled | legal_AU = Scheduled as illegal from June 2018
| legal_US = unscheduled | legal_US = unscheduled
| legal_UK = unscheduled | legal_UK = unscheduled
| routes_of_administration = oral | routes_of_administration = ]
| pregnancy_category = N/A


<!--Identifiers--> <!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = <!-- blanked - oldvalue: 317318-70-0 --> | CAS_number = 317318-70-0
| ATC_prefix = none
| PubChem = 9803963 | PubChem = 9803963
| ChemSpiderID = 7979723
⚫ | ChEMBL_Ref = {{ebicite|correct|EBI}}
| UNII_Ref = {{fdacite|correct|FDA}}
| ChEMBL = <!-- blanked - oldvalue: 38943 -->
| UNII = 7I2HA1NU22
| IUPHAR_ligand = 2687
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 73726
⚫ | ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 38943

<!--Chemical data-->
| C=21 | H=18 | F=3 | N=1 | O=3 | S=2 | C=21 | H=18 | F=3 | N=1 | O=3 | S=2
⚫ | smiles = O=C(COc1ccc(SCc2c(C)nc(c3ccc(C(F)(F)F)cc3)s2)cc1C)O
| molecular_weight = 453.498 g/mol
| StdInChI = 1S/C21H18F3NO3S2/c1-12-9-16(7-8-17(12)28-10-19(26)27)29-11-18-13(2)25-20(30-18)14-3-5-15(6-4-14)21(22,23)24/h3-9H,10-11H2,1-2H3,(H,26,27)
⚫ | smiles = O=C(O)COc1c(C)cc(SCC2=C(C)N=C(c3ccc(C(F)(F)F)cc3)S2)cc1
| StdInChIKey = YDBLKRPLXZNVNB-UHFFFAOYSA-N
}} }}


'''GW501516''' (also known as '''GW-501,516''', '''GW1516''', '''GSK-516''', '''Cardarine''', and on the ] as '''Endurobol'''<ref name=convo>{{cite web | vauthors = Koh B |url=http://theconversation.com/anti-doping-agency-warns-cheats-on-the-health-risks-of-endurobol-12997|title=Anti-doping agency warns cheats on the health risks of Endurobol |publisher=The Conversation|date=2013-03-22}}</ref>) is a ] ] that was invented in a collaboration between ] and ] in the 1990s. It entered into clinical development as a drug candidate for ] and ], but was abandoned in 2007 because ] showed that the drug caused cancer to develop rapidly in several organs.<ref name="Sahebkar2014rev" />
'''GW-501516''' (also known as '''GW-501,516''','''GW1516''' or '''GSK-516''') is a ] modulator compound being investigated for drug use by ].<ref name="pmid12699745">{{cite journal | author = Sznaidman ML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR Jr, Sternbach DD | title = Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity | journal = Bioorg. Med. Chem. Lett. | volume = 13 | issue = 9 | pages = 1517–21 | year = 2003 | month = May | pmid = 12699745 | doi = 10.1016/S0960-894X(03)00207-5 | url = | issn = }}</ref><ref name="pmid17869249">{{cite journal | author = Dimopoulos N, Watson M, Green C, Hundal HS | title = The PPARdelta agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilisation or insulin sensitivity in rat L6 skeletal muscle cells | journal = FEBS Lett. | volume = 581 | issue = 24 | pages = 4743–8 | year = 2007 | month = October | pmid = 17869249 | doi = 10.1016/j.febslet.2007.08.072 | url = | issn = }}</ref> It activates the same pathways activated through exercise, including PPARδ and ]. It is being investigated as a potential treatment for ], ], ] and ]. <ref name="pmid16511591">{{cite journal | author = Barish GD, Narkar VA, Evans RM | title = PPAR delta: a dagger in the heart of the metabolic syndrome | journal = J. Clin. Invest. | volume = 116 | issue = 3 | pages = 590–7 | year = 2006 | month = March | pmid = 16511591 | pmc = 1386117 | doi = 10.1172/JCI27955 | url = | issn = }}</ref> <ref name="doi:10.1210/me.2003-0151">{{cite journal | author =

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 ] for the drug candidate and to its abuse by athletes as a ]. The ] (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.

==History==
GW501516 was initially discovered during a research collaboration between ] and ] that began in 1992.<ref>{{cite news|title=GW501516 GlaxoSmithKline, Ligand milestone payment.|date=28 June 2004|publisher=R & D Focus Drug News}}</ref> The discovery of the compound was published in a 2001 issue of '']''.<ref name="pmid14677574">{{cite journal | vauthors = Wolf G | s2cid = 12362203 | title = The function of the nuclear receptor peroxisome proliferator-activated receptor delta in energy homeostasis | journal = Nutr. Rev. | volume = 61 | issue = 11 | pages = 387–90 |date=November 2003 | pmid = 14677574 | doi = 10.1301/nr.2003.nov.387-390 | doi-access = free }}</ref> Oliver ''et&nbsp;al.'' reported that they used "] and ]" to develop it.<ref name="pmid11309497">{{cite journal | vauthors = 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 | title = A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 9 | pages = 5306–11 |date=April 2001 | pmid = 11309497 | pmc = 33205 | doi = 10.1073/pnas.091021198 | bibcode = 2001PNAS...98.5306O | doi-access = free }}</ref> One of the authors was the son of ] who discovered ] in the 1960s.<ref name=flynn>{{cite news|url=https://www.wsj.com/articles/0,,SB107644751774825922,00|title=Father and Son: In Two Generations, Drug Research Sees a Big Shift|publisher=The Wall Street Journal| vauthors = Flynn J |date=11 February 2004}}{{Dead link|date=July 2018 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

''R & D Focus Drug News'' reported that GSK began ] of the compound for the treatment of ] in 2000<ref>{{cite news|title=GW501516 Glaxo Wellcome phase change I, UK|date=20 November 2000|publisher=R & D Focus Drug News}}</ref> followed by phase I/II in 2002.<ref>{{cite news|title=GW501516 GlaxoSmithKline phase change II, UK|date=25 February 2002|publisher=R & D Focus Drug News}}</ref> In 2003, Ligand Pharmaceuticals earned a $1&nbsp;million payment as a result of GSK continuing phase I development.<ref>{{cite news|url=http://www.businesswire.com/news/home/20030604005732/en/Ligand-Earns-1-Million-Milestone-Payment-GlaxoSmithKline|title=Ligand Pharmaceuticals Incorporated Earns $1 Million Milestone Payment as GlaxoSmithKline Advances Development of 501516|date=5 June 2003|publisher=Reuters Significant Developments}}</ref>

By 2007, GW501516 had completed two phase II clinical studies and other studies relating to ], ], ] and ],<ref name="Barish_2006">{{cite journal | vauthors = Barish GD, Narkar VA, Evans RM | title = PPAR delta: a dagger in the heart of the metabolic syndrome | journal = The Journal of Clinical Investigation | volume = 116 | issue = 3 | pages = 590–7 | date = March 2006 | pmid = 16511591 | pmc = 1386117 | doi = 10.1172/JCI27955 }}</ref><ref name="dressel">{{cite journal | vauthors = Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, Muscat GE | title = 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 | journal = Molecular Endocrinology | volume = 17 | issue = 12 | pages = 2477–93 | date = December 2003 | pmid = 14525954 | doi = 10.1210/me.2003-0151 | name-list-style = amp | doi-access = free }}</ref> but GSK abandoned further development of the drug in 2007 for reasons which were not disclosed at the time.<ref name="pmid18808307">{{cite journal | vauthors = Billin AN | title = PPAR-beta/delta agonists for Type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home | journal = Expert Opinion on Investigational Drugs | volume = 17 | issue = 10 | pages = 1465–71 | date = October 2008 | pmid = 18808307 | doi = 10.1517/13543784.17.10.1465 | s2cid = 86564263 }}</ref> It later emerged that the drug was discontinued because ] showed that the drug caused cancer to develop rapidly in several organs, at dosages of 3&nbsp;mg/kg/day in both mice and rats.<ref name="Sahebkar2014rev">{{cite journal | vauthors = Sahebkar A, Chew GT, Watts GF | title = New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease | journal = Expert Opinion on Pharmacotherapy | volume = 15 | issue = 4 | pages = 493–503 | date = March 2014 | pmid = 24428677 | doi = 10.1517/14656566.2014.876992 | s2cid = 21158696 | quote = 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 }}</ref><ref>{{cite conference | conference = 48th Annual Meeting of the Society of Toxicology | location = Baltimore | url = http://www.toxicology.org/AI/Pub/Tox/2009Tox.pdf | archive-url = https://web.archive.org/web/20150504013406/http://www.toxicology.org/AI/PUB/Tox/2009Tox.pdf | archive-date = 2015-05-04 | title = PS 895 - Rat carcinogenicity study with GW501516, a PPAR delta agonist | vauthors = Geiger LE, Dunsford WS, Lewis DJ, Brennan C, Liu KC, Newsholme SJ | date = 2009 | publisher = ] | page = 105 }}</ref><ref>{{cite conference | conference = 48th Annual Meeting of the Society of Toxicology | location = Baltimore | url = http://www.toxicology.org/AI/Pub/Tox/2009Tox.pdf | archive-url = https://web.archive.org/web/20150504013406/http://www.toxicology.org/AI/PUB/Tox/2009Tox.pdf | archive-date = 2015-05-04 | title = PS 896 - Mouse carcinogenicity study with GW501516, a PPAR delta agonist. | vauthors = Newsholme SJ, Dunsford WS, Brodie T, Brennan C, Brown M, Geiger LE | date = 2009 | publisher = ] | page = 105 }}</ref>

]'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.<ref>{{cite journal | vauthors = Fan W, Waizenegger W, Lin CS, Sorrentino V, He MX, Wall CE, Li H, Liddle C, Yu RT, Atkins AR, Auwerx J, Downes M, Evans RM | title = PPARδ Promotes Running Endurance by Preserving Glucose | journal = Cell Metabolism | volume = 25 | issue = 5 | pages = 1186–1193.e4 | date = May 2017 | pmid = 28467934 | pmc = 5492977 | doi = 10.1016/j.cmet.2017.04.006 }}</ref> The work was published in 2007 in '']'' and was widely reported in the popular press including ''The New York Times'' and ''The Wall Street Journal''.<ref name=behar>{{cite web|url=http://www.outsideonline.com/outdoor-adventure/natural-intelligence/Faster--Higher--Squeakier-.html?page=all|title=Faster. Higher. Squeakier.|publisher=Outside magazine|vauthors=Bezar M|date=2011-11-01|access-date=2013-04-02|archive-date=2012-08-27|archive-url=https://web.archive.org/web/20120827091907/http://www.outsideonline.com/outdoor-adventure/natural-intelligence/Faster--Higher--Squeakier-.html?page=all|url-status=dead}}</ref>

Another human study (comparing cardarine with the PPARα agonist ] and placebo) was published in 2021.<ref>{{cite journal | vauthors = Park J, Kim JY |title=Cardarine (GW501516) Effects on Improving Metabolic Syndrome |journal=Journal of Health, Sports, and Kinesiology |date=30 July 2021 |volume=2 |issue=2 |pages=22–27 |doi=10.47544/johsk.2021.2.2.22|doi-access=free }}</ref>

===Performance-enhancing drug===
⚫ Concerns were raised prior to the ] that GW501516 could be used by athletes as a ] 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 ]. The ] (WADA) developed a test for GW501516 and other related ] modulators,<ref name="The Independent">{{cite web | url = https://www.independent.co.uk/life-style/health-and-wellbeing/health-news/warning-to-beijing-olympics-over-pills-that-mimic-exercise-882608.html | title = Warning to Beijing Olympics over pills that mimic exercise | vauthors = Laurance J, Rajan A | date = 2008-08-01 | work = Health News, Health & Wellbeing | publisher = The Independent | access-date = 2008-08-01 }}</ref> and added such drugs to the prohibited list in 2009.<ref> {{webarchive |url=https://web.archive.org/web/20090203030039/http://www.wada-ama.org/rtecontent/document/2009_Prohibited_List_ENG_Final_20_Sept_08.pdf |date=February 3, 2009 }}</ref>

GW501516 has been promoted on ] and athletics websites<ref name=newsci>{{cite news|url=https://www.newscientist.com/article/mg21729103-400-anti-doping-agency-warns-athletes-of-black-market-drug/|title=Anti-doping agency warns athletes of black market drug |publisher=New Scientist|date=2013-03-26}}</ref> and by 2011 had already been available for some time on the ].<ref name=convo/><ref name="pmid21538997">{{cite journal | vauthors = Thevis M, Geyer H, Thomas A, Schänzer W | title = 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 | journal = Drug Test Anal | volume = 3 | issue = 5 | pages = 331–6 |date=May 2011 | pmid = 21538997 | doi = 10.1002/dta.283 }}</ref> In 2011, it was reported to cost $1,000 for 10 g.<ref name=behar/> In 2012, WADA recategorised GW501516 from a ] compound to a "hormone and metabolic modulator".<ref name="pmid22130396">{{cite journal | vauthors = Sanchis-Gomar F, Lippi G | title = Telmisartan as metabolic modulator: a new perspective in sports doping? | journal = J Strength Cond Res | volume = 26 | issue = 3 | pages = 608–10 |date=March 2012 | pmid = 22130396 | doi = 10.1519/JSC.0b013e31824301b6 | doi-access = free }}</ref>


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 '']'' attributed the warning to the risks of the drug causing cancer.<ref name= newsci/><ref name=wada13>{{cite web|url=https://www.wada-ama.org/en/media/news/2013-03/wada-issues-alert-on-gw501516|title=WADA issues alert on GW501516|publisher=World Anti-Doping Agency|date=2013-03-21|archive-url=https://web.archive.org/web/20130602050612/http://playtrue.wada-ama.org/news/wada-issues-alert-on-gw501516/|archive-date=June 2, 2013}}</ref>
* Uwe Dressel,
* Tamara L. Allen,
* Jyotsna B. Pippal,
* Paul R. Rohde,
* Patrick Lau,
* and George E. O. Musc


A number of athletes have tested positive for GW501516. At the ] 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.<ref>{{cite web | vauthors = Stokes S | url = http://www.velonation.com/News/ID/14381/GW501516-positives-confirmed-three-of-four-riders-are-from-same-BCR-Pizza-Hut-team.aspx | title = GW501516 positives confirmed, three of four riders are from same BCR Pizza Hut team | work = velonation.com | date = 15 April 2013 }}</ref><ref>{{cite web | vauthors = Stokes S | url = http://www.velonation.com/News/ID/15125/Four-riders-each-handed-two-year-bans-for-use-of-GW501516.aspx | title = Four riders each handed two year bans for use of GW501516 | work = velonation.com | date = 30 July 2013 }}</ref><ref> {{webarchive |url=https://web.archive.org/web/20140715214800/http://www.uci.ch/Modules/BUILTIN/getObject.asp?MenuId=MTU3Mjg&ObjTypeCode=FILE&type=FILE&id=Nzk5OTY&LangId=1 |date=July 15, 2014 }}, uci.ch</ref> In April 2013, Russian cyclist ] was suspended by cycling's governing body ] after having tested positive for GW501516. Kaykov's team ] dismissed him immediately<ref>{{cite news|url=https://www.bbc.co.uk/sport/0/cycling/22111802|title=European champion Valery Kaykov sacked for failing drug test|publisher=BBC|date=2013-04-11|access-date=2013-04-11}}</ref> and in May 2013, Venezuelan ] was provisionally suspended by the Lampre team.<ref>{{cite news|url=http://www.uci.ch/Modules/ENews/ENewsDetails.asp?source=SiteSearch&id=OTI3Ng&MenuId=MTI2Mjg|archive-url=https://archive.today/20130628075943/http://www.uci.ch/Modules/ENews/ENewsDetails.asp?source=SiteSearch&id=OTI3Ng&MenuId=MTI2Mjg|url-status=dead|archive-date=2013-06-28|title=Miguel Ubeto Aponte provisionally suspended|publisher=UCI|date=2013-05-13|access-date=2013-05-15}}</ref> In February 2014, Russian race walker ] tested positive for GW501516.<ref name=List20140626></ref><ref>Associated Press: , espn.com, 11 July 2014</ref> In April 2019, American heavyweight boxer ] tested positive for GW501516 which caused his challenge for ]'s World Heavyweight titles to be cancelled.<ref>{{cite web| url=http://www.espn.com/boxing/story/_/id/26561763/big-baby-miller-failed-three-drug-tests| title=Sources: 'Big Baby' Miller failed three drug tests| vauthors = Rafael D | author-link=Dan Rafael| work=]| date=2019-04-19| access-date=2019-04-21}}</ref> In December 2020, Miller was suspended for 2 years for repeated violations.<ref>{{cite news |title=Heavyweight Miller gets 2-year PED suspension |url=https://www.espn.co.uk/boxing/story/_/id/30436921/heavyweight-jarrell-miller-gets-2-year-suspension-ped-violation |access-date=13 July 2022 |work=ESPN.com |date=2 December 2020 |language=en}}</ref> In July 2022, the 2012 800{{nbs}}m Olympic silver medalist from Botswana, ] tested positive for GW501516 and was provisionally suspended just days before the ].<ref>{{cite news |title=London 2012 medallist Nijel Amos suspended after positive doping test |url= https://www.washingtonpost.com/sports/olympics/2024/07/11/issam-asinga-lawsuit-gatorade-doping-ban/ |access-date=13 July 2024|work=the Guardian |date=13 July 2022 |language=en}}</ref> Surinam's ], who set the under-20 world track record in the men's 100 meters, was informed on Aug. 9, 2023 by the ] 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 ] provided him with Gatorade Recovery Gummies at their awards ceremony one week earlier in Los Angeles tainted with GW501516.<ref>{{cite news |title= Teen sprinter sues Gatorade over doping ban that cost him an Olympic spot|url=https://www.theguardian.com/sport/2022/jul/13/london-2012-medallist-nijel-amos-suspended-after-positive-doping-test |access-date=12 July 2022 |work=The Washington Post |date=11 July 2022 |language=en}}</ref>
at | title = 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 | journal = Molecular Endocrinology | issue =17 | pages = 2477-93 | year = 2003 doi=doi:10.1210/me.2003-015 | url = }}</ref>
GW-501516 has a synergistic effect when combined with ]: the combination has been shown to significantly increase exercise endurance in animal studies more than either compound alone.
<ref name="Narkar_2008">{{cite journal | author = 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,2 Evans RM | title = AMPK and PPARδ Agonists Are Exercise Mimetics | journal = Cell | volume = 134 | issue = 3| pages = 1–11 | year = 2008 | month = August| doi = 10.1016/j.cell.2008.06.051 | url = http://download.cell.com/pdfs/0092-8674/PIIS0092867408008386.pdf |format=PDF| issn = | pmid = 18674809 | pmc = 2706130 }}</ref><ref name="urlExercise In A Pill: Researchers Identify Drugs That Enhance Exercise Endurance">{{cite web | url = http://www.sciencedaily.com/releases/2008/07/080731135918.htm | title = Exercise In A Pill: Researchers Identify Drugs That Enhance Exercise Endurance | author = | authorlink = | coauthors = | date = 2008-08-01 | format = | work = Science News | publisher = ScienceDaily | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-08-01}}</ref>


==Mode of action==
GW-50156 regulates fat burning through a number of widespread mechanisms <ref> Normal 0 false false false EN-US X-NONE X-NONE http://www.sciencedirect.com/science/article/pii/S0092867403002691 </ref>; it increases ] in ] tissue and increases muscle gene expression, especially genes involved in preferential lipid utilization.,<ref name="AMPK and PPARδ Agonists Are Exercise Mimetics">Vihang A. Narkar, Michael Downes, Ruth T. Yu, Emi Embler, Yong-Xu Wang, Ester Banayo, Maria M. Mihaylova, Michael C. Nelson, Yuhua Zou, Henry Juguilon, Heonjoong Kang, Reuben J. Shaw, Ronald M. Evans, AMPK and PPARδ Agonists Are Exercise Mimetics, Cell, Volume 134, Issue 3, 8 August 2008, Pages 405-415, ISSN 0092-8674, 10.1016/j.cell.2008.06.051.
GW501516 is a selective ] (activator) of the ] receptor.<ref name="pmid16625823">{{cite journal | vauthors = Pelton P | title = GW-501516 GlaxoSmithKline/Ligand | journal = Current Opinion in Investigational Drugs | volume = 7 | issue = 4 | pages = 360–70 | date = April 2006 | pmid = 16625823 }}</ref> It displays high affinity (K<sub>i</sub> = 1 nM) and potency (EC<sub>50</sub> = 1 nM) for PPARδ with greater than {{nowrap|1,000-fold}} selectivity over ] and ].<ref name="pmid11309497"/>
(http://www.sciencedirect.com/science/article/pii/S0092867408008386)}}</ref><ref name="pmid17500064">{{cite journal | author = Krämer DK, Al-Khalili L, Guigas B, Leng Y, Garcia-Roves PM, Krook A | title = Role of AMP kinase and PPARdelta in the regulation of lipid and glucose metabolism in human skeletal muscle | journal = J. Biol. Chem. | volume = 282 | issue = 27 | pages = 19313–20 | year = 2007 | month = July | pmid = 17500064 | doi = 10.1074/jbc.M702329200 | url = | issn = }}</ref> <ref> Normal 0 false false false EN-US X-NONE X-NONE http://mend.endojournals.org/content/17/12/2477.short </ref> This shift changes the body's metabolism to favor burning fat for energy instead of carbohydrates or muscle protein, potentially allowing clinical application for obese patients to lose fat effectively without experiencing muscle catabolism or the effects and satiety issues associated with low blood sugar. <ref> http://mend.endojournals.org/content/17/12/2477.short </ref> GW-501516 also increases muscle mass, which improved glucose tolerance and reduced fat mass accumulation even in mice fed a very high fat diet, suggesting that GW-501516 may have a protective effect against obesity <ref> Normal 0 false false false EN-US X-NONE X-NONE http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0020294 </ref>


In rats, binding of GW501516 to PPARδ recruits the ] ]. The PPARδ/coactivator complex in turn upregulates the expression of proteins involved in energy expenditure.<ref name="Sprecher_2007"/> Furthermore, in rats treated with GW501516, increased fatty acid metabolism in skeletal muscle and protection against diet-induced obesity and ] was observed. In obese rhesus monkeys, GW501516 increased ] (HDL) and lowered ] (VLDL).<ref name="Sprecher_2007">{{cite journal | vauthors = Sprecher DL | title = Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta | journal = The American Journal of Cardiology | volume = 100 | issue = 11 A | pages = n20-4 | date = December 2007 | pmid = 18047848 | doi = 10.1016/j.amjcard.2007.08.009 }}</ref>
It has been demonstrated at oral doses of 5 mg a day to reverse metabolic abnormalities in ] men with pre-diabetic ], most likely by stimulating fatty acid oxidation.<ref name="pmid18024853">{{cite journal | author = Risérus U, Sprecher D, Johnson T, Olson E, Hirschberg S, Liu A, Fang Z, Hegde P, Richards D, Sarov-Blat L, Strum JC, Basu S, Cheeseman J, Fielding BA, Humphreys SM, Danoff T, Moore NR, Murgatroyd P, O'Rahilly S, Sutton P, Willson T, Hassall D, Frayn KN, Karpe F | title = Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men | journal = Diabetes | volume = 57 | issue = 2 | pages = 332–9 | year = 2008 | month = February | pmid = 18024853 | doi = 10.2337/db07-1318 | url = | issn = }}</ref> Treatments with GW-501516 have been shown to increase HDL cholesterol by up to 79% in rhesus monkeys and the compound is now undergoing Phase II trials to improve HDL cholesterol in humans. <ref> Normal 0 false false false EN-US X-NONE X-NONE http://scholar.googleusercontent.com/scholar?q=cache:tJeBg7cljugJ:scholar.google.com/&hl=en&as_sdt=0,39 </ref>


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 ]-associated ] by increasing inflammation and the expression of ] and ].<ref>{{cite journal | vauthors = Zhou D, Jin J, Liu Q, Shi J, Hou Y | title = PPARδ agonist enhances colitis-associated colorectal cancer | journal = European Journal of Pharmacology | volume = 842 | pages = 248–254 | date = January 2019 | pmid = 30391747 | doi = 10.1016/j.ejphar.2018.10.050 }}</ref> See also {{section link|PPARδ|Role in cancer}}.
⚫ Concerns were raised prior to the ] that GW-501516 could be used by athletes as a ] which 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 ].<ref name="AICAR and GW1516 - The Exercise Pill">{{cite web |url= http://www.medical-weight-loss-guide.com/AICAR.html | title= AICAR and GW 1516 - The Exercise Pill |accessdate=2008-09-18 |work= |publisher= |date= }}</ref> The ] has also begun work on a test GW-501516 and other related ] modulators.,<ref name="urlWarning to Beijing Olympics over pills that mimic exercise - Health News, Health & Wellbeing - The Independent">{{cite web | url = http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/warning-to-beijing-olympics-over-pills-that-mimic-exercise-882608.html | title = Warning to Beijing Olympics over pills that mimic exercise | author = Laurance J, Rajan A | authorlink = | coauthors = | date = 2008-08-01 | format = | work = Health News, Health & Wellbeing | publisher = The Independent | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-08-01 }}</ref> and they have been added to the prohibited list from 2009 onwards.<ref></ref> The compound has yet to be named a controlled or prohibited substance by any nation's drug enforcement or regulation agency. To date, no athlete is known to have tested positive for the substance, though the increase in endurance, muscle fiber performance, fat loss and metabolism suggests GW-501516 has the potential for ] use and abuse.


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