Enobosarm

• Molecular FormulaC₁₉H₁₄F₃N₃O₃
• Average mass389.328 Da

(2S)-3-(4-Cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide

(2S)-3-(4-Cyanophénoxy)-N-[4-cyano-3-(trifluorométhyl)phényl]-2-hydroxy-2-méthylpropanamide

841205-47-8[RN]

GTx-024, MK 2866, Ostarine[Trade name]

Enobosarm, also known as ostarine or MK-2866, is an investigational selective androgen receptor modulator (SARM) developed by GTx, Inc. for the treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merck & Company.

Chemistry

According to a 2009 paper authored by GTx, “Readers are cautioned to note that the name ostarine is often mistakenly linked to the chemical structure of [S-4], which is also known as andarine. The chemical structure of ostarine has not been publicly disclosed.”^[2] A 2009 review stated “Recently, GTx disclosed that compound 5 had advanced into clinical trials. The patent application described detailed data in an initial proof-of-concept Phase IIa clinical trial. It is not explicitly stated that compound 5 is Ostarine (MK-2866).^[3]

As of 2012, the mechanism of action of Enobosarm is still being debated and requires further investigation.^[4]

Enobosarm is in phase II clinical studies for the treatment of metastatic breast cancer. It has been in phase III clinical trials for the treatment of muscle wasting in patients with non-small cell lung cancer. However, this research has been discontinued.

Enobosarm was discovered by University of Tennessee, then licensed to GTx later. It was granted fast track designation by FDA in 2013 for treatment of muscle wasting in patients with non-small cell lung cancer. Route 1

1. US20070123563A1.

2. US20100249228A1.

3. US2014080905A1.

4. US20070173546A1. Route 2

1. US20070123563A1.2. US20100249228A1.

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Clinical data
Other names	GTx-024; MK-2866; Ostarine; S-22[1]
Routes of administration	By mouth
ATC code	none
Legal status
Legal status	US: Investigational New Drug
Pharmacokinetic data
Elimination half-life	24 hours[citation needed]
Identifiers
showIUPAC name
CAS Number	841205-47-8
PubChem CID	11326715
ChemSpider	9501667
UNII	O3571H3R8N
KEGG	D10221
CompTox Dashboard (EPA)	DTXSID30233006
Chemical and physical data
Formula	C19H14F3N3O3
Molar mass	389.334 g·mol−1
3D model (JSmol)	Interactive image
Melting point	132 to 136 °C (270 to 277 °F)
showSMILES
showInChI

History

GTx Incorporated was founded in Memphis in 1997 and licensed rights to enobosarm from the University of Tennessee Research Foundation; the SARM compounds were invented by James T. Dalton, Duane D. Miller, Karen A. Veverka and their research teams at Ohio State University, the University of Tennessee and GTx, respectively.^[5]

By 2007, enobosarm was in a Phase II trial, and that year GTx signed an exclusive license agreement for its SARM program with Merck & Co.^[6] The companies ended the deal in 2010.^[7]

In August 2011, there was a double-blind, placebo controlled phase II trial that focused on elderly men and postmenopausal women which concluded that Enobosarm showed statistically significant improvements in total lean body mass and physical function without the negative side effects that are normally present with steroids.^[8]

In August 2013, GTx announced that enobosarm had failed in two Phase III clinical trials to treat wasting in people with lung cancer.^[9] The company had invested around $35 million in the development of the drug.^[10] The company said at that time that it planned to pursue approval of enobosarm in Europe; the company was also still developing GTx-758 for castration-resistant prostate cancer.^[11]

In 2016, GTx began Phase II trials, to see if enosobarm might be effective to treat stress urinary incontinence in women.^[12]

In 2018, GTx announced the Phase II trials on Enobosarm’s efficacy on stress urinary incontinence^[13] in women failed to achieve its primary endpoint in the ASTRID Trial.

Health effects

The FDA has warned that SARMs can have serious side effects ranging from risk of heart attack to stroke and liver damage.^[14]

Society and culture

Doping

SARMs including Enobosarm may be and have been used by athletes to assist in training and increase physical stamina and fitness, potentially producing effects similar to anabolic steroids. For this reason, SARMs were banned by the World Anti-Doping Agency in January 2008, despite no drugs from this class yet being in clinical use, and blood tests for all known SARMs have been developed.^[15][16] There are a variety of known cases of doping in sports with enobosarm by professional athletes.

Further information: List of doping in sport cases § Enobosarm

In May 2017, Dynamic Technical Formulations voluntarily recalled all lots of Tri-Ton, a dietary supplement that the USFDA tested and found to contain Enobosarm and andarine.^[17]

In October 2018, UFC fighter Sean O’Malley tested positive for Enobosarm and was suspended by the Nevada State Athletic Commission and USADA for six months. O’Malley tested positive again on May 25, 2019 and was suspended for nine months by the same agencies. USADA determined that none of O’Malley’s positive tests were consistent with intentional use and he was allowed to compete at UFC 248 as long as he kept his levels below the threshold of 100 ng/ml.^[18]

On January 7, 2019, the College National Football Championship was played between University of Alabama and Clemson University. Prior to the College Football National Championship game, three Clemson players who were suspended — Dexter Lawrence, Braden Galloway and Zach Giellaall — tested positive for a substance known as Enobosarm (ostarine). On June 23, 2019 Clemson did not release ostarine investigation findings, citing privacy law.^[19]

In July 2019, National Football League player Taylor Lewan failed a drug test for Enobosarm, which Lewan claimed he ingested accidentally as an unlabeled ingredient in a supplement.^[20]

On October 23, 2020, the Union Cycliste Internationale (UCI) announced that the Italian rider Matteo Spreafico has been notified of two adverse analytical findings (AAFs) for Enobosarm in two samples collected during the Giro d’Italia on 15–16 October 2020.^[21]

On July 6, 2021, during the 2020 Summer Olympics, Brazil women’s national volleyball team player Tandara was temporarily suspended for testing positive for Ostarine. The test was carried out and identified by the Brazilian Doping Control Authority (ABDC).^[22]

On August 12, 2021, after the 2020 Summer Olympics, Chijindu “CJ” Ujah, A member of the silver medal-winning British 4×100 relay team was temporarily suspended for testing positive for both Ostarine and S-23. The sample was collected post event by the International Testing Agency and confirmed two days later as positive. The case was referred to the anti-doping division of the Court of Arbitration for Sport.^[23] Finally in February 2022, Great Britain were stripped of their silver medal.^[24]

In October 2021, two Thoroughbred horses named Arafat and Komunist tested positive for ostarine after races at Woodbine Racetrack. In a decision of the Alcohol and Gaming Commission of Ontario issued May 30, 2022, the horses were declared unplaced in the races in question, and their trainer Robert Gerl was fined $100,000 (as well as forfeiting prize money) and suspended from racing for 20 years.^[25]

In May 2022, National Football League Wide Receiver DeAndre Hopkins was suspended six games without pay by the NFL for violating the league’s performance-enhancing drug policy. According to Hopkins, he tested positive for ostarine.^[26]

Wider use

In recent years, ostarine and related substances have increasingly become used by the general public as “gym supplements” such as pre-workout or lifestyle drugs, rather than as an aid to performance in athletic or bodybuilding competitions. In 2018, analysis of a fatberg from a sewer in central London showed ostarine to be the most abundant pharmaceutical drug detected, and was present at higher concentration than recreational drugs such as MDMA and cocaine. While this isolated result may not be representative of overall levels of use, for ostarine to be detectable in sewer deposits reflects significant levels of ostarine use in the area close to where the sample was collected.^[27]

See also

• List of investigational sex-hormonal agents § Androgenics

References

1. ^ “Enobosarm – GTx”. Adis Insight. Springer Nature Switzerland AG. Retrieved 25 April 2018.
2. ^ Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, et al. (June 2009). “Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit”. Journal of Medicinal Chemistry. 52 (12): 3597–617. doi:10.1021/jm900280m. PMID 19432422.
3. ^ Zhang X, Lanter JC, Sui Z (September 2009). “Recent advances in the development of selective androgen receptor modulators”. Expert Opinion on Therapeutic Patents. 19 (9): 1239–58. doi:10.1517/13543770902994397. PMID 19505196. S2CID 46186955. The first quoted sentence is cited to Published PCT application WO2008127717
4. ^ Dubois V, Laurent M, Boonen S, Vanderschueren D, Claessens F (May 2012). “Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions”. Cellular and Molecular Life Sciences. 69 (10): 1651–67. doi:10.1007/s00018-011-0883-3. PMID 22101547. S2CID 17276140.
5. ^ WO 2005120483, Dalton JT, Mille DD, Veverka KA, “Selective androgen receptor modulators and methods of use thereof”, published 22 December 2005, assigned to University of Tennessee Research Foundation
6. ^ Nagle M (7 November 2007). “Merck flexes muscle with GTx deal”. Outsourcing Pharma.
7. ^ Swanekamp K (15 March 2010). “Merck And GTx Go Their Separate Ways”. Forbes.
8. ^ Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, et al. (September 2011). “The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial”. Journal of Cachexia, Sarcopenia and Muscle. 2 (3): 153–161. doi:10.1007/s13539-011-0034-6. PMC 3177038. PMID 22031847.
9. ^ “Enobosarm fails endpoints in Ph III study”. The Pharma Letter. 20 August 2013.
10. ^ Sheffield M (April 4, 2014). “Steiner resigns from GTx”. Memphis Business Journal.
11. ^ Garde D (4 April 2014). “GTx’s CEO finds the door as the company moves on from a PhIII failure”. FierceBiotech.
12. ^ “GTx begins Phase II trial of enobosarm to treat women with stress urinary incontinence”. Drug Development Technology. 14 January 2016. Archived from the original on 22 June 2016.
13. ^ “GTx’s Enobosarm Fails Phase II Trial in Stress Urinary Incontinence; Stock Plunges 90%+”. Genetic Engineering & Biotechnology News. Retrieved 1 August 2019.
14. ^ “FDA In Brief: FDA warns against using SARMs in body-building products”. Retrieved 1 August 2019.
15. ^ Thevis M, Kohler M, Schlörer N, Kamber M, Kühn A, Linscheid MW, Schänzer W (May 2008). “Mass spectrometry of hydantoin-derived selective androgen receptor modulators”. Journal of Mass Spectrometry. 43 (5): 639–50. Bibcode:2008JMSp…43..639T. doi:10.1002/jms.1364. PMID 18095383.
16. ^ Thevis M, Kohler M, Thomas A, Maurer J, Schlörer N, Kamber M, Schänzer W (May 2008). “Determination of benzimidazole- and bicyclic hydantoin-derived selective androgen receptor antagonists and agonists in human urine using LC-MS/MS”. Analytical and Bioanalytical Chemistry. 391 (1): 251–61. doi:10.1007/s00216-008-1882-6. PMID 18270691. S2CID 206899531.
17. ^ “Dynamic Technical Formulations, LLC. Issues a Voluntary Nationwide Recall of Tri-Ton Due to the Presence of Andarine and Ostarine”. U.S. Food & Drug Administration. May 19, 2017.
18. ^ Raimondi M (January 22, 2020). “NSAC: Sean O’Malley can fight at UFC 248 in March after serving suspension”. ESPN. Retrieved June 9, 2020.
19. ^ Needelman J (14 September 2020). “Clemson lineman suspended by ncaa for positive ostarine test opens up for first time”. Retrieved November 13, 2020.
20. ^ Bieler D (25 July 2019). “Failed PED test has a highly paid offensive lineman sharing polygraph results”. Washington Post. Retrieved 25 July 2019. One of the NFL’s highest-paid offensive linemen claimed Wednesday that he did not knowingly take a banned substance he says got him a four-game suspension — and he took a polygraph test in an attempt to prove it.
21. ^ “UCI statement on Matteo Spreafico”. Union Cycliste Internationale (UCI). 22 October 2020. Retrieved 2020-10-23.
22. ^ “Tandara é suspensa por “potencial violação” do antidoping e está fora das Olimpíadas”.
23. ^ “Tokyo Olympics: Team GB 4x100m relay silver medallist CJ Ujah suspended for suspected doping violation”.
24. ^ “CJ Ujah: Great Britain lose Tokyo Olympics relay medal after doping violation”. BBC. 18 February 2022.
25. ^ “IN THE MATTER OF THE HORSE RACING LICENCE ACT, 2015, S.0.2015,c.38,Sched.9; AND IN THE MATTER OF Robert Gerl” (PDF). Retrieved 2 June 2022.
26. ^ “Cardinals WR DeAndre Hopkins still hopes to reduce six-game suspension”. NFL.com. 23 June 2022.
27. ^ Saner E (24 April 2018). “Why there are more gym supplements in a London fatberg than cocaine and MDMA”. The Guardian.

//////////GTx-024, MK 2866, Ostarine, enobosarm

O=C(NC1=CC=C(C#N)C(C(F)(F)F)=C1)[C@](C)(O)COC2=CC=C(C#N)C=C2