GW501516 (also known as GW-501,516, GW1516, GSK-516, Cardarine, and on the
black market
A black market, underground economy, or shadow economy is a clandestine market or series of transactions that has some aspect of illegality or is characterized by noncompliance with an institutional set of rules. If the rule defines the se ...
as Endurobol
) is a
PPARδ
Peroxisome proliferator-activated receptor delta (PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1 (NUC1) is a nuclear receptor that in humans is encoded by the ''PPARD'' gene.
This gene encodes a member of the peroxisome pr ...
receptor agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an ...
that was invented in a collaboration between
Ligand Pharmaceuticals
Ligand Pharmaceuticals is a biopharmaceutical company located in San Diego, California. Founded in 1987 as Progenix Inc., the company went public in 1992. Initially focused on developing its own drugs, a period of turbulence in the early 2000s cul ...
and
GlaxoSmithKline
GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...
in the 1990s. It entered into clinical development as a drug candidate for
metabolic
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
and
cardiovascular diseases
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...
, but was abandoned in 2007 because
animal testing
Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
showed that the drug caused cancer to develop rapidly in several organs.
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
A black market, underground economy, or shadow economy is a clandestine market or series of transactions that has some aspect of illegality or is characterized by noncompliance with an institutional set of rules. If the rule defines the se ...
for the drug candidate and to its abuse by athletes as a
doping agent
A dopant, also called a doping agent, is a trace of impurity element that is introduced into a chemical material to alter its original electrical or optical properties. The amount of dopant necessary to cause changes is typically very low. When ...
. The
World Anti-Doping Agency
The World Anti-Doping Agency (WADA; french: Agence mondiale antidopage, AMA) is a foundation initiated by the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against drugs in sports. The agency's key ...
(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
GSK and
Ligand Pharmaceuticals
Ligand Pharmaceuticals is a biopharmaceutical company located in San Diego, California. Founded in 1987 as Progenix Inc., the company went public in 1992. Initially focused on developing its own drugs, a period of turbulence in the early 2000s cul ...
that began in 1992. The discovery of the compound was published in a 2001 issue of ''
PNAS
''Proceedings of the National Academy of Sciences of the United States of America'' (often abbreviated ''PNAS'' or ''PNAS USA'') is a peer-reviewed multidisciplinary scientific journal. It is the official journal of the National Academy of Scien ...
''.
Oliver ''et al.'' reported that they used "
combinatorial chemistry Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individua ...
and
structure-based drug design
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activ ...
" to develop it.
One of the authors was the son of
Leo Sternbach
Leo Sternbach (May 7, 1908 – September 28, 2005) was a Polish American chemist who is credited with first synthesizing benzodiazepines, the main class of tranquilizers.
Background and family
Sternbach was born on May 7, 1908, in Opatija, K ...
who discovered
benzodiazepines
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, i ...
in the 1960s.
''R & D Focus Drug News'' reported that GSK began
phase I trials
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
of the compound for the treatment of
hyperlipidemia
Hyperlipidemia is abnormally elevated levels of any or all lipids (fats, cholesterol, or triglycerides) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also used as an umbre ...
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
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
,
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
,
dyslipidemia
Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...
and
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
,
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
Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
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
Ronald Mark Evans (born April 17, 1949 in Los Angeles, California) is an American Biologist, Professor and Head of the Salk’s Gene Expression Laboratory, and the March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute fo ...
'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
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
'' and was widely reported in the popular press including ''The New York Times'' and ''The Wall Street Journal''.
Performance-enhancing drug
Concerns were raised prior to the
2008 Beijing Olympics
The 2008 Summer Olympics (), officially the Games of the XXIX Olympiad () and also known as Beijing 2008 (), were an international multisport event held from 8 to 24 August 2008, in Beijing, China. A total of 10,942 athletes from 204 Nat ...
that GW501516 could be used by athletes as an
ergogenic
Performance-enhancing substances, also known as performance-enhancing drugs (PEDs), are substances that are used to improve any form of activity performance in humans. A well-known example of cheating in sports involves doping in sport, where bann ...
performance-enhancing drug
Performance-enhancing substances, also known as performance-enhancing drugs (PEDs), are substances that are used to improve any form of activity performance in humans. A well-known example of cheating in sports involves doping in sport, where bann ...
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 International Olympic Committee (IOC; french: link=no, Comité international olympique, ''CIO'') is a non-governmental sports organisation based in Lausanne, Switzerland. It is constituted in the form of an association under the Swiss ...
. The
World Anti-Doping Agency
The World Anti-Doping Agency (WADA; french: Agence mondiale antidopage, AMA) is a foundation initiated by the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against drugs in sports. The agency's key ...
(WADA) developed a test for GW501516 and other related
PPARδ
Peroxisome proliferator-activated receptor delta (PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1 (NUC1) is a nuclear receptor that in humans is encoded by the ''PPARD'' gene.
This gene encodes a member of the peroxisome pr ...
modulators,
and added such drugs to the prohibited list in 2009.
GW501516 has been promoted on
bodybuilding
Bodybuilding is the use of progressive resistance exercise to control and develop one's muscles (muscle building) by muscle hypertrophy for aesthetic purposes. It is distinct from similar activities such as powerlifting because it focuses ...
and athletics websites
and by 2011 had already been available for some time on the
black market
A black market, underground economy, or shadow economy is a clandestine market or series of transactions that has some aspect of illegality or is characterized by noncompliance with an institutional set of rules. If the rule defines the se ...
.
In 2011, it was reported to cost $1,000 for 10 g.[ In 2012, WADA recategorised GW501516 from a ]gene doping
Gene doping is the hypothetical non-therapeutic use of gene therapy by athletes in order to improve their performance in those sporting events which prohibit such applications of genetic modification technology, and for reasons other than the treat ...
compound to a "hormone and metabolic modulator".
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
''New Scientist'' is a magazine covering all aspects of science and technology. Based in London, it publishes weekly English-language editions in the United Kingdom, the United States and Australia. An editorially separate organisation publishe ...
'' 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
The Vuelta Ciclista a Costa Rica (''English'': Tour of Costa Rica) is a bicycle racing stage race held annually since 1965 in Costa Rica. The men's Vuelta carries a UCI rating of 2.2 and is part of the UCI America Tour, which is one of six UCI C ...
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
Valery Kaykov (born 7 May 1988) is a Russian former professional racing cyclist.
Track
In 2010 Kaykov won the individual pursuit at the U-23 European Track Championships. He was also part of the Russian team that won the team pursuit.
At the 20 ...
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
-->
Miguel is a given name and surname, the Portuguese and Spanish form of the Hebrew name Michael. It may refer to:
Places
* Pedro Miguel, a parish in the municipality of Horta and the island of Faial in the Azores Islands
* São Miguel (disam ...
was provisionally suspended by the Lampre team. In February 2014, Russian race walker Elena Lashmanova
Elena Anatolyevna Lashmanova (russian: Елена Анатольевна Лашманова, born 9 April 1992 in Saransk, Mordovia) is a Russian race walker. In March 2022 she accepted a two-year ban, retroactive to March 2021, and all of her re ...
tested positive for GW501516.[Sanctioned athletes list – 26 June 2014]
/ref> In April 2019, heavyweight boxer Jarrell Miller
Jarrell Miller (born July 15, 1988) is an American professional boxer and former kickboxer who competes in the heavyweight division. He first came to prominence in 2007 when he competed for the New Jersey Tigers in the World Combat League and ...
tested positive for GW501516 which caused his challenge for Anthony Joshua
Anthony Oluwafemi Olaseni Joshua (born 15 October 1989) is an English professional boxer. He is a two-time former unified world heavyweight champion, having held the WBA (Super), IBF, WBO, and IBO titles twice between 2016 and 2021. At r ...
'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, Nijel Amos
Nijel Carlos Amilfitano Amos (born 15 March 1994) is a Motswana middle-distance runner who competes in the 800 metres. He won silver at the 2012 Summer Olympics, which was Botswana's first ever Olympic medal.
Early life
Nijel Amos is from Ma ...
tested positive for GW501516 and was provisionally suspended just days before the 2022 World Athletics Championships
The 2022 World Athletics Championships was the eighteenth edition of the World Athletics Championships. It was held at Hayward Field in Eugene, Oregon, United States, from July 15–24, 2022, with the country hosting that competition for the f ...
.
Mode of action
GW501516 is a selective agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
(activator) of the PPARδ
Peroxisome proliferator-activated receptor delta (PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1 (NUC1) is a nuclear receptor that in humans is encoded by the ''PPARD'' gene.
This gene encodes a member of the peroxisome pr ...
receptor. It displays high affinity (Ki = 1 nM) and potency (EC50 = 1 nM) for PPARδ with > 1,000 fold selectivity over PPARα
Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gene ...
and PPARγ
Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance
receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...
.
In rats, binding of GW501516 to PPARδ recruits the coactivator
A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA p ...
PGC-1α
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the ''PPARGC1A'' gene. PPARGC1A is also known as human accelerated region 20 ( HAR20). It may, therefore, have played a key ro ...
. 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
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
was observed. In obese rhesus monkeys, GW501516 increased high-density lipoprotein
High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are ty ...
(HDL) and lowered very-low-density lipoprotein
Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, low-density lipo ...
(VLDL).
See also
* Acadesine
* GFT505
Elafibranor (International nonproprietary name, INN, code name GFT505) is an experimental medication that is being studied and developed by Genfit for the treatment of cardiometabolic diseases including Diabetes mellitus, diabetes, insulin resist ...
* GW0742
GW0742 (also known as GW610742) is a PPARδ/β agonist that is investigated for drug use by GlaxoSmithKline.
Pharmacology Pharmacodynamics
It is mixed PPAR-B agonist antagonist depending on its dosage. It has weak activity on multiple nuclear ...
* Irisin
Fibronectin type III domain-containing protein 5, the precursor of irisin, is a type I transmembrane glycoprotein that is encoded by the FNDC5 gene. Irisin is a cleaved version of FNDC5, named after the Greek messenger goddess Iris.
Fibronectin ...
* Peroxisome proliferator-activated receptor
In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regu ...
* Sodelglitazar
Sodelglitazar, formerly known as GW 677954, is a thiazole PPARδ receptor agonist developed by GlaxoSmithKline. While it is primarily active at the PPARδ receptor, it is considered a pan agonist with activity at PPARα and PPARγ receptors.
Sa ...
* SR9009
SR9009, also known as Stenabolic, is a research drug that was developed by professor Thomas Burris of the Scripps Research Institute as an agonist of Rev-ErbA (i.e., increases the constitutive repressor, repression of Regulation of gene expressi ...
References
{{PPAR modulators
PPAR agonists
GSK plc brands
Carcinogens
Experimental drugs
Trifluoromethyl compounds
Thioethers
Thiazoles
Carboxylic acids