Enobosarm

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"Ostarine" redirects here. For the chemical structure mistakenly linked to the name, see Andarine.
Enobosarm
Clinical data
Other namesOstarine; GTx-024; MK-2866; S-22; VERU-024[1]
Routes of
administration		By mouth[2]
ATC code
  • None
Legal status
Legal status
UGT1A1, UGT2B7[4]
MetabolitesEnobosarm glucuronide[4]
Elimination half-life14–24 hours[5][6][4][7]
ExcretionFeces (70%), urine (21–25%) (rats)[3]
Identifiers
  • ((2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide)
JSmol)
Melting point132 to 136 °C (270 to 277 °F)
  • O=C(NC1=CC=C(C#N)C(C(F)(F)F)=C1)[C@](C)(O)COC2=CC=C(C#N)C=C2
  • InChI=1S/C19H14F3N3O3/c1-18(27,11-28-15-6-2-12(9-23)3-7-15)17(26)25-14-5-4-13(10-24)16(8-14)19(20,21)22/h2-8,27H,11H2,1H3,(H,25,26)/t18-/m0/s1
  • Key:JNGVJMBLXIUVRD-SFHVURJKSA-N
  (verify)

Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a

muscle strength.[11][2][12][10][13] As a result, enobosarm was not approved and development for this use was terminated.[2] Enobosarm is taken by mouth.[2]

Known possible

prostate gland and seminal vesicles.[7][10][2][18][19] The AR-mediated effects of enobosarm in many other androgen-sensitive tissues are unknown.[18][20]

Enobosarm was first identified in 2004[11] and has been under clinical development since at least 2005.[1][18] It is the most well-studied SARM of all of the agents that have been developed.[21] According to GTx, its developer, a total of 25 clinical studies have been carried out on more than 1,700 people involving doses from 1 to 100 mg as of 2020.[10][22] However, enobosarm has not yet completed clinical development or been approved for any use.[1][2] As of November 2023, it is in phase 3 clinical trials for the treatment of breast cancer and is in phase 2 studies for improvement of body composition in people taking GLP-1 receptor agonists.[1][9] Enobosarm was developed by GTx, Inc., and is now being developed by Veru, Inc.[1]

Aside from its development as a potential

safety.[17] Many products sold online that are purported to be enobosarm either contain none or contain other unrelated substances.[17][25] Social media has played an important role in facilitating the widespread non-medical use of SARMs.[26]

Medical uses

Enobosarm is not approved for any medical use and is not available as a licensed

pharmaceutical drug as of 2023.[1][2][10][17]

Side effects

General

fatigue, anemia, nausea, diarrhea, and back pain.[6][27][14]

Enobosarm has shown

LDL cholesterol levels are unchanged.[16][17][28] In healthy elderly men, total testosterone levels decreased significantly at doses of 1 and 3 mg/day (-31% and -57%, respectively), whereas levels of free testosterone, dihydrotestosterone (DHT), estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) did not change significantly at doses up to 3 mg/day.[16][28] In healthy postmenopausal women, LH and FSH decreased significantly only at the 3 mg/day dose (-17% and -30%, respectively), whereas levels of total testosterone, free testosterone, DHT, and estradiol did not clearly change relative to placebo.[16][17][28] SHBG levels were lowered at doses of 1 to 3 mg/day, decreasing dramatically by 61% in men and by 80% in women at the 3 mg/day dose.[16][17][28] For comparison, testosterone enanthate by intramuscular injection at a highly supraphysiological dose of 600 mg/week resulted in only a 31% decrease in SHBG levels.[28][29] Despite the large changes in SHBG levels, levels of free testosterone did not significantly change in either men or women.[16][17][28] Small but significant increases in hemoglobin and hematocrit, and small but significant decreases in fasting blood glucose, insulin levels, and insulin resistance, have been observed with enobosarm at 3 mg/day.[17][30][28][6]

In small short-term (3-month) clinical trials in healthy elderly or postmenopausal women, enobosarm at doses ranging from 0.1 to 3 mg/day had mixed effects on

growth or cause hirsutism.[31][28] These effects are measures of androgenic action in skin and hair follicles.[31] In the first study, at doses of 0.1 to 3 mg/day, there were no significant changes relative to placebo in sebum tape scores with enobosarm and there were no consistent increases in Ferriman–Gallwey score, with most women having no change in score or a decreased score and only one having an increase in score.[31][28] In the second study, which employed 3 mg/day enobosarm, there was a significant 1.25-fold increase in sebum production from baseline and a significant 1.5-fold increase in sebum production relative to placebo.[31] No differences in sebaceous gland volume were apparent upon histological examination in this study.[31]

At doses ranging from 0.1 to 18 mg/day in clinical trials, enobosarm has been associated with

17α-alkylated anabolic steroids.[12]

SARMs are often advertised and sold on the Internet at doses higher than have been described in the literature.

estrogen deficiency with consequences like bone loss among others, and, due to suppression of the hypothalamic–pituitary–gonadal axis (HPG axis), may cause infertility.[17]

Anecdotal reports of masculinization with SARMs in women exist in online forums.[26]

The

liver damage and has warned against their use in bodybuilding products.[41]

Overdose

Enobosarm has been assessed in clinical trials at doses ranging from 0.1 to 18 mg/day.

pharmacokinetic studies and doses of up to 30 mg/day have been given in short 14-day pharmacokinetic studies.[5] Enobosarm sold via black-market Internet suppliers and used non-medically is often taken at much higher doses than those used widely in clinical trials (e.g., 10–30 mg/day), with unknown adverse effects and risks.[17][27]

Interactions

Enobosarm is a

BCRP substrate).[4] Based on the preceding findings, it was concluded that enobosarm poses low risk for clinically relevant drug interactions.[4]

Pharmacology

Pharmacodynamics

Enobosarm is a

prosexual effects in male rats comparable to those of the synthetic androgen and anabolic steroid fluoxymesterone as well.[2][47][50]

The

exogenous AR agonists, for instance virilization and prostate growth.[47][49][54][55]

In animal studies, enobosarm has shown potent muscle-promoting effects that were similar to those of testosterone and DHT.[7][10][56][57][58][48] In one of the first published studies, enobosarm maximally restored prostate weight to 51%, seminal vesicle weight to 98%, and levator ani muscle weight to 136% in castrated male rats relative to gonadally intact control male rats, with an ED50 dose for muscle of 0.03 mg/day.[56][51][48] For comparison, testosterone propionate was able to maximally stimulate levator ani muscle to 104% and prostate weight to 121%, with ED50 doses of 0.15 mg/day and 0.13 mg/day, respectively.[7] Hence, enobosarm was able to stimulate the levator ani muscle to a size greater than that in normal male rats or produced with exogenous testosterone in castrated male rats, but was only capable of partially rescuing prostate gland weight.[51][48][7] Additionally, enobosarm fully maintained or restored levator ani weight at doses that did not affect LH or FSH levels in gonadally intact animals (≤0.1 mg/day).[7] As such, it was more potent in stimulating muscle than testosterone at doses that did not affect gonadotropin levels.[5][7] In gonadally intact male rats, enobosarm significantly increased levator ani muscle weight to 131% of intact controls but significantly decreased the weights of the prostate gland and seminal vesicles, demonstrating an antagonistic or partially agonistic effect in these tissues.[7] In another animal study, enobosarm and DHT increased levator ani weights to similar or slightly different extents in intact male rats, but DHT strongly increased prostate weight while enobosarm reduced prostate weight.[7][59][58] Aside from effects in muscle tissue, enobosarm has been assessed and found to completely maintain bone quality and composition in castrated male rats and to partially but not fully prevent bone loss in ovariectomized female rats, indicating potent anabolic effects in bone as well.[7]

In a phase 2 human clinical trial in healthy elderly men and postmenopausal women, enobosarm dose-dependently increased lean body mass (muscle mass) across doses of 0.1, 0.3, 1, and 3 mg/day, with a significant 1.3 kg gain over placebo at 3 mg/day and a non-significant 0.7 kg gain over placebo at 1 mg/day.[10][28] Similarly, in two phase 3 clinical trials in men and postmenopausal women with muscle wasting due to non-small-cell lung cancer, enobosarm at 3 mg/day significantly increased lean body mass by 0.41 kg and 0.47 kg.[10] However, enobosarm did not successfully increase muscle strength in these phase 3 trials.[10] In any case, it has been suggested that the study designs and physical function outcomes in such trials may have been flawed.[60][61][62][63][2] The increases in lean body mass that have been seen with employed doses of enobosarm in clinical trials are very modest compared to those produced with supraphysiological doses of testosterone over similar timeframes (e.g., 0.5–1.5 kg with enobosarm versus 5–8 kg with 300–600 mg/week intramuscular testosterone enanthate in healthy young men).[53][17][64] The effects of higher doses of enobosarm (9–18 mg/day) on lean body mass and muscle strength are also being evaluated in women with breast cancer.[2][43] There is some evidence that women may be more sensitive to lean body mass increases with SARMs, specifically GSK-2881078 but potentially also others like enobosarm, than men.[10][17]

In addition to its mixed agonist–antagonist activity at the AR, enobosarm is likely to also differ from steroidal androgens in its effects due to differences in within-tissue ligand metabolism.

17α-alkylated anabolic steroids like stanozolol.[20][68][69] It can be attributed to the first pass through the liver with oral administration and to the high oral bioavailability and strong resistance to hepatic metabolism of these agents.[20][70][71][12]

Enobosarm has no estrogenic activity, either intrinsic to itself or via its metabolites.[31][7][18][20][42] As a result, the drug is not expected to have feminizing effects or risk of gynecomastia (breast development) nor to stimulate estrogen-sensitive breast cancer.[18][7] SARMs like enobosarm are not ideal agents for androgen replacement therapy as they are not expected to reproduce the full spectrum of effects of testosterone and other androgens, including not only AR-mediated effects but also notably aromatization into estrogen and required physiological estrogenic effects in bone and brain.[20] Enobosarm has been found to be a weak antagonist of the progesterone receptor and hence might have some capacity for antiprogestogenic effects.[5][7] Aside from its weak interaction with the progesterone receptor, enobosarm is highly selective for the AR and does not bind to other nuclear hormone receptors.[7]

Pharmacokinetics

Absorption

Enobosarm is

steady-state peak of 68.1 ng/mL following repeated 3 mg doses.[46][4] The pharmacokinetics of enobosarm are linear and proportional over a dose range of 1 to 100 mg in single doses in healthy men.[5][7] The pharmacokinetics of enobosarm are similar in young versus elderly individuals.[7] A concentration–time curve of enobosarm levels following a single oral dose of enobosarm in humans has been published.[7]

Distribution

Enobosarm is a

seminal vesicles.[3] This is consistent with enobosarm producing centrally mediated effects in humans like suppression of LH and FSH secretion.[16][17][28]

Enobosarm does not bind to sex hormone-binding globulin.[18]

Metabolism

UGT1A1 and UGT2B7.[4] Enobosarm glucuronide is the primary circulating metabolite of enobosarm.[4]

Coadministration of the strong CYP3A4

substrate of CYP3A4 and UGT enzymes.[4]

The metabolism of enobosarm is similar to that of the closely structurally related drug bicalutamide.[3]

Elimination

In rats, enobosarm was excreted approximately 70% in feces and 21 to 25% in urine.[3]

Enobosarm has an

terminal half-life was 22.0 ± 5.8 (SD) hours, with a range of 13.7 to 31.3 hours in different individuals[4]

Chemistry

Enobosarm is a

molecular weight = 389.3 g/mol) and highly lipophilic (predicted log P = 2.7–3.3) compound.[72][73]

Enobosarm and related SARMs like

structural analogues of bicalutamide.[18][78][79][80] Bicalutamide was used to derive acetothiolutamide, andarine was developed from acetothiolutamide, the SARM S-1 was developed from andarine, and finally enobosarm was developed from S-1.[81] Bicalutamide is used clinically as an antiandrogen, but there is some evidence that bicalutamide itself may have some SARM-like properties in certain tissues, for instance in muscle and bone.[82][83][84]

Enobosarm (S-22) and andarine (S-4) and their chemical structures have sometimes been confused.[85] The chemical structure of enobosarm was not disclosed until November 2011.[47][85]

Novel nonsteroidal antiandrogens have been developed from enobosarm with enhanced potency and activity relative to conventional antiandrogens like bicalutamide and enzalutamide.[86][87]

History

The first SARMs were arylpropionamides derived from the

pharmaceutical drug.[1][89]

A phase 1 clinical trial employing enobosarm had been completed by 2005.[18] By 2007, enobosarm was in a phase 2 trial, and that year GTx signed an exclusive license agreement for its SARM program with Merck & Co.[94] The companies ended the deal in 2010.[95] In August 2011, there was a 12-week double-blind, placebo controlled phase 2 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 apparent adverse effects on hair growth or sebum production.[28] In August 2013, GTx announced that enobosarm had failed in two phase 3 clinical trials to treat wasting in people with lung cancer.[96] The company had invested around $35 million in the development of the drug.[97] The company said at that time that it planned to pursue approval of enobosarm in Europe; the company was also still developing GTx-758, a nonsteroidal estrogen, for castration-resistant prostate cancer.[98] As of 2018, enobosarm was the only SARM to have reached or completed phase 3 clinical trials.[51]

In 2016, GTx began phase 2 trials, to see if enobosarm might be effective to treat

metastatic breast cancer.[101] In January 2024, Veru Inc. submitted an Investigational New Drug application to the FDA of enobosarm for prevention of muscle loss and augmentation of fat loss in combination with glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide for weight loss.[9] In addition, they announced plans to conduct a phase 2b study of enobosarm at doses of 3 to 6 mg/day for this purpose in sarcopenic obese or overweight elderly individuals receiving GLP-1 receptor agonists.[9]

Enobosarm was developed by GTx, Inc., and is now being developed by Veru, Inc.[1]

Society and culture

Names

Enobosarm is the

International Nonproprietary Name (INN).[102] Ostarine was a tentative brand name of the drug created by GTx, Inc. that did not end up being used for marketing purposes but continues to be used as a synonym for the drug.[1][6] Enobosarm is also known by the pharmaceutical developmental code names S-22 (synthesis paper), GTx-024 (GTx, Inc.), MK-2866 (Merck), and VERU-024 (Veru, Inc.).[1]

Non-medical use

Enobosarm and other SARMs are sold by black-market vendors on the Internet.

LGD-4033 (VK5211; "ligandrol"), and andarine (GTx-007; S-4).[26] Many products sold online that are purported to be enobosarm either contain none or contain other unrelated substances, and doses are also frequently not as labeled.[17][25] Social media has played an important role in facilitating the widespread non-medical use of SARMs.[26]

Doping in sport

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

doping in sports with enobosarm by professional athletes
.

List of doping cases

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 FDA tested and found to contain Enobosarm and andarine.[105]

In October 2018,

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.[106]

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. On June 23, 2019 Clemson did not release enobosarm investigation findings, citing privacy law.[107]

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.[108]

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.[109]

On July 6, 2021, during the 2020 Summer Olympics, Brazil women's national volleyball team player Tandara was temporarily suspended for testing positive for enobosarm. The test was carried out and identified by the Brazilian Doping Control Authority (ABDC).[110]

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 enobosarm and S-23. The sample was collected post event by the International Testing Agency (ITA) and confirmed two days later as positive. The case was referred to the anti-doping division of the Court of Arbitration for Sport.[111] Finally in February 2022, Great Britain were stripped of their silver medal.[112] In October 2022, Ujah was suspended for 22 months by the ITA.[113]

In October 2021, two Thoroughbred horses named Arafat and Komunist tested positive for enobosarm 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.[114]

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 enobosarm.[115]

In April 2023, British boxer Amir Khan was banned for two years after an anti-doping test revealed the presence of enobosarm following his fight against Kell Brook in February 2022.[116]

Research

Enobosarm is currently under development for the treatment of breast cancer.[1][8][44][45] It was also previously under development for a variety of other potential uses, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy or sarcopenia, and stress incontinence.[1][10][2] However, development for all other indications has been discontinued.[1]

Enobosarm was assessed for the treatment of

muscle strength, as measured by stair climb power.[11][2][12][13] Consequent to these findings, enobosarm did not gain regulatory approval, and development for this use was terminated.[2] Enobosarm had originally been under development for the treatment of sarcopenia (age-related muscle atrophy).[10] However, the FDA requested a cardiovascular safety study be conducted to proceed with phase 3 trials for this indication.[10] The developer of enobosarm refused to conduct this study due to the considerable costs that would be involved.[10] Instead, it opted to trial enobosarm for muscle wasting in cachexia patients, in whom the FDA was more tolerant to cardiovascular side effects and did not require cardiovascular safety evaluation.[10]

Following negative findings for muscle wasting, enobosarm was evaluated for the treatment of

pelvic floor muscles.[1][2] Enobosarm reached phase 2 clinical trials for this indication, but development was discontinued due to lack of effectiveness in a phase 2 study.[1][2]

Subsequently, enobosarm was repurposed again for the treatment of androgen receptor-positive (AR+) estrogen receptor-positive (ER+) breast cancer.[1][8] As of November 2023, it is in phase 3 clinical trials for the treatment of this type of breast cancer.[1][44][45] Increases in lean body mass and muscle strength as a secondary benefit with enobosarm are also being evaluated in these women.[2][43] These trials are notably employing several-fold higher doses of enobosarm than were assessed in the muscle wasting phase 3 trials (9 mg/day versus 3 mg/day, respectively).[2][43]

In January 2024, it was announced that enobosarm was being developed for prevention of muscle wasting and augmentation of fat loss in combination with glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide for weight loss.[9] A phase 2b clinical trial for this indication with 3 to 6 mg/day enobosarm in sarcopenic obese or overweight elderly individuals is being prepared.[9]

According to GTx, the original developer of enobosarm, a total of 25 clinical studies have been carried out on more than 1,700 people involving doses from 1 to 100 mg as of 2020.[10][22] However, enobosarm has not yet completed clinical development or been approved for any use.[1][2]

See also

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v "Enobosarm - GTx". Adis Insight. Springer Nature Switzerland AG. Retrieved 22 December 2023.
  2. ^
    PMID 32257854
    . Unfortunately, results of recent clinical trials of the SARM GTx-024 (Enobosarm) have tempered expectations for its utility as a therapy for muscle wasting. Early on, GTx-024 appeared to have a very bright future as a treatment for sarcopenia/cachexia. Preliminary clinical trials demonstrated that GTx-024 could increase lean body mass and improve physical function without androgenic side effects (27). However, Enobosarm was dealt a blow after the phase III Prevention and treatment Of muscle Wasting in patients with cancER (POWER) I and II trials, where increases in lean body mass were once again observed, but without improved stair climb power (79,80). Failure to attain both primary endpoints led to a lack of approval by the Food and Drug Administration (FDA), which has cast doubt on the previously charted course for SARMs and has tempered enthusiasm regarding the role of SARMs in the treatment of muscle wasting conditions.
  3. ^
    S2CID 6545249
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  4. ^
    S2CID 24200291
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  5. ^
    PMID 24490605
    . Pharmacokinetics & metabolism: Enobosarm was shown to have linear pharmacokinetics in single-dose studies in healthy male subjects using doses of 1, 3, 10, 30 and 100 mg. In another study enobosarm was given to healthy subjects at doses of 1, 3, 10 and 30 mg over 14 days. Per data from GTx, Inc., the halflife ranged from 14–21 h with similar mean maximum plasma concentration and exposure in subjects of varying ages (Table 1) [20].
  6. ^
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  9. ^ a b c d e f "Veru Submits IND Application to FDA for the Development of Enobosarm to Prevent Muscle Loss While Augmenting Fat Loss in Combination with GLP-1 Drugs for Weight Loss". BioSpace. 8 January 2024.
  10. ^
    S2CID 219174372
    . [...] to proceed with enobosarm into a phase III clinical trial in patients with sarcopenia, the FDA requested a cardiovascular safety study, which the manufacturer refused to undertake due to considerable costs and decided to test enobosarm in cancer cachexia patients in whom the FDA was more tolerant to the long-term cardiovascular side effects [67]. [...] Enobosarm promotes a similar anabolic response compared with DHT via muscle AR activation, [...] [35]. In a recent study with ovariectomized mice, the weight of the musculus gastrocnemius has been shown to be higher in all groups treated with ostarine as well as bone mineral density and bone biomechanical properties [15]. Moreover, the stimulation of reproductive organs with enobosarm seems to be less pronounced compared to testosterone administration [36] due to its partial agonist and antagonist effect on other androgen-dependent tissues such as prostate and seminal vesicles [37]. [...] In the POWER trials (POWER 1, NCT01355484 and POWER 2, NCT01355497; Table 1), double-blind, placebo-controlled, and multi-center phase III studies [40], patients with non-small-cell lung cancer were given 3 mg of enobosarm or placebo for five months. Despite a lower rate of decline in body weight in the group treated with enobosarm in POWER 1, patients increased LBM at day 84 and day 147 in POWER 1 (+0.41 kg) and POWER 2 (+0.47 kg) compared with patients receiving placebo. However, no physical function improvement has been reported in both studies [41].
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    S2CID 43199715
    . Enobosarm has also been evaluated in two phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer 1 and 2 (POWER1 (NCT01355484) and POWER2 (NCT01355497)). [...] The co-primary endpoints of this trial were lean body mass (LBM) response and physical function response for enobosarm vs. placebo after 3 months of treatment. Beneficial effects on both LBM and physical function were found in POWER1, and benefit to LBM but equivocal effects on physical function were found in POWER2.
  12. ^
    PMID 36479151
    . 17α-alkylated AASs have been modified to be more resistant to liver degradation so that they have decreased first-pass metabolism, allowing for better oral bioavailability and more stable serum levels. However, reduced liver clearance increases the potential for hepatotoxicity.19 Much like this class of AASs, SARMs have been designed for adequate oral bioavailability with decreased liver degradation which would likely create a similar potential for hepatotoxicity.8,15 [...] Ostarine was the first SARM to undergo a phase III clinical trial. The POWER1 and POWER2 trials were two identical randomized, double-blind, placebo-controlled studies to evaluate the efficacy of Ostarine for the treatment of muscle wasting in non-small cell lung cancer. Participants were given 3 mg of Ostarine versus placebo. No study results were published; but GTx Incorporated reported that Ostarine failed to meet endpoints for improvement in lean body mass and physical function compared with placebo.
  13. ^ a b c d "GTX Reports Results for Enobosarm POWER Trials for the Prevention and Treatment of Muscle Wasting in Patients with Non-Small Cell Lung Cancer" (Press release). 19 August 2013.
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    PMID 33672087
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  15. ^
    PMID 30503797
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  16. ^
    S2CID 8104778
    . Anabolic androgenic steroids (AASs) comprise synthetic derivatives of testosterone. AASs bind directly to the cytosolic androgen receptor (AR), which is widely distributed across reproductive and non-reproductive tissues, including the prostate, skeletal muscle, liver, skin, and central nervous system (CNS). This binding results in various physiological activities [1], the major one being a masculinizing effect in the skeletal muscle via muscle building [2].
  17. ^
    S2CID 225049089
    . Additionally, reported SARM-induced fat free mass increases are a mere fraction of that reported in modest doses of testosterone derivatives in similar timeframes (~1.5kg versus ~7kg in SARMs and testosterone, respectively) [21].
  18. ^
    S2CID 96279138
    .
  19. ^
    PMID 25722318
    . Selective AR modulators (SARMs) are a class of drugs in development; unlike androgen synthesis inhibitors, they act as selective androgen agonists and show promise as a potential therapeutic strategy in BCa. Enobosarm (GTx024) is the farthest along in clinical development, and demonstrates an agonist effect that in some populations inhibits BCa growth. Preclinical data show antitumor activity of GTx-024 in ARC stably expressing cell lines MCF-7 (ERC) and MDA-MB-231 (TNBC) implanted subcutaneously into nude mice. Tumor growth was reduced more than 75% in MDA-MB-231-AR cells and 50% in MCF-7-AR cells compared with vehicle-treated tumors, demonstrating benefit (Dalton et al. 2013).
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  22. ^ a b "GTx, Inc. Release: Enobosarm Meets Pre-Specified Primary Efficacy Endpoint In Ongoing Phase 2 Clinical Trial In ER+/AR+ Breast Cancer". BioSpace. 28 November 2016. Enobosarm, a selective androgen receptor modulator (SARM) has been evaluated in 24 completed or ongoing clinical trials enrolling over 1,500 subjects, of which approximately 1,000 subjects were treated with enobosarm at doses ranging from 0.1 mg to 100 mg.
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    PMID 37571268
    . Common low-grade side effects of ostarine include headache, nausea, fatigue, and back pain. Other observed effects include increases in alanine transaminase and decreases in HDL, blood glucose, and insulin resistance, all of which returned to normal upon stopping ostarine treatment [1,35]. Information from bodybuilding forums and fitness enthusiasts cited 10 mg to 30 mg daily as the optimal dose for a minimum of 12 weeks, which is 10 times higher than the clinically studied dose, with anecdotal evidence suggesting that taking ostarine for much longer than this can suppress free T levels [1].
  28. ^
    PMID 22031847
    . The reductions in SHBG [with enobosarm] in men and women (−61% and −80%, respectively, at the 3-mg dose) exceed those observed in men treated with a 600-mg intramuscular testosterone enanthate (−31%) [41].
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    . The next invention was that of the first non-steroidal androgen by Dalton et al. [111] in 1998, six decades after the first non-steroidal estrogen [112]. This creates a new class of non-steroidal synthetic androgen, often termed Specific Androgen Receptor Modulators (SARM), a misleading marketing term rather than an accurate pharmacological description [113,114], usurping a speculative but unsound analogy with Specific Estrogen Receptor Modulators (SERM). [...] none of the non-steroidal androgens under development [116,117] are marketed by 2021. Yet hope springs eternal for this new attempt to separate anabolic from androgenic properties of androgens to facilitate marketing for muscle wasting and other selective effects of testosterone.
  40. PMID 21511988
    . Although development of the first nonsteroidal androgens (17, 18) as candidate selective AR modulators (19) raises hope of resurrecting this defunct term (20), prereceptor activation mechanisms cannot apply to nonsteroidal androgens, and the singular AR lacks a dual drive mechanism of the other paired sex steroid receptors. Consequently, it is not surprising that available knowledge (21) provides only slender hope that this failed, and probably false, dichotomy will now succeed through a renewed search guided by the same in vivo bioassay.
  41. ^ "FDA In Brief: FDA warns against using SARMs in body-building products". Retrieved 1 August 2019.
  42. ^
    PMID 27729416
    .
  43. ^
    S2CID 58234934
    . It is worth noting that SARMs were initially developed to get benefit of their anabolic effect on muscle and bone without much harm to other tissues. One randomized controlled trial [28], recruited male and females with cancer and weight loss showed that enobosarm 1 mg or 3 mg was associated with significant increase in lean body mass compared to placebo. This led to another ongoing trial, with more selection, aiming to evaluate enobosarm (with higher doses 9 or 18 mg) effect on physical function and lean body mass of ER+/AR+ breast cancer patients (NCT02463032). Such additional action of this class of drugs carries major hope for patients with AR-positive advanced breast cancer, where weight loss, muscle weakness and physical inactivity represent a big challenge for the patient's quality of life (QOL).
  44. ^
    PMID 37946721
    .
  45. ^
    PMID 37684290
    .
  46. ^
    PMID 27885819
    . New information on elimination kinetics and potential drug-drug interactions of the SARM GTx-024 (Enobosarm, Ostarine, S-22, MK-2866) was presented by Coss et al. indicating maximum plasma concentrations of the intact drug and its glucuronic acid conjugate of ca. 60 and 100 ng/mL, respectively, reached between 1 and 2 h following an oral dose of 3 mg.[85] The CYP3A4 inhibitor itraconazole did not affect pharmacokinetic parameters of GTx-024, while the CYP3A4 inducer rifampin reduced maximum plasma concentrations significantly. Conversely, the UGT-inhibitor probenecid increased levels of both GTx-024 and its glucuronide.
  47. ^
    S2CID 2584722
    . The structure and name of Ostarine (GTx-024, MK-2866, Enobosarm, S-22) were disclosed by the USAN Council in November 2011 to establish it as a first member of a new class of drugs furthest in clinical development (Structure 2 in Scheme 1).
  48. ^
    S2CID 30799845
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  49. ^
    PMID 20444881
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  50. PMID 17023534
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  51. ^
    PMID 28624515
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  52. ^
    PMID 17339601
    .
  53. ^
    PMID 19357508
    . At the doses that have been tested, the first generation SARMs induce modest gains in lean body mass in healthy volunteers, which are nowhere near the much greater gains in skeletal muscle mass reported with supraphysiological doses of testosterone. The modest gains of 1.0 to 1.5 kg in fat-free mass with first generation SARMs over 4–6 weeks should be contrasted with the 5–7 kg gains in fat-free mass with 300 and 600 mg doses of testosterone enanthate. However, it is possible that next generation of SARM molecules will have greater potency and selectivity than the first generation SARMs.
  54. ISBN 978-3-031-31500-8
    . Physiologically N/C interaction is indispensable because it delays ligand dissociation from the receptor, protects the ligand binding pocket, and prevents receptor degradation [118]. That N/C interaction is essential in AR physiology is demonstrated by the identification of AR LBD mutations resulting in androgen insensitivity syndromes (AIS) that disrupt N/C interaction without affecting the equilibrium binding affinity for the ligand [119, 120].
  55. PMID 12051960
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  56. ^
    S2CID 35120033
    . Enobosarm was discovered in 2004 as a hyper-myoanabolic SARM that dissociated the anabolic from androgenic effects of AR in terms of potency (ED50) and efficacy (Emax) [29]. Levator ani muscle weight was increased to 131 and 136% of intact controls in intact and castrated (maintenance mode) rats, respectively, without significant increases in ventral prostate and seminal vesicles weights. Importantly, increases in levator ani muscle weight were associated with increases in muscle strength (soleus) in rats. Enobosarm also exerted in-vivo osteoanabolic effects alone and synergistically with alendronate in terms of bone density, strength, and structure [30], which was explained by in-vitro mechanistic studies that demonstrated antiresorptive (osteoclast inhibition) and anabolic (osteoblast differentiation) effects [31].
  57. PMID 26393303
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  58. ^
    PMID 18801930
    .
  59. S2CID 245941791
    . Similar to other N-arylpropionamide SARMs, in male rats treated for 14 days at 1 mg/day dose S-22 (17) exhibited increased levator ani muscle weight but significantly reduced prostate weight [...]
  60. PMID 28807233
    .
  61. PMID 33759397
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  62. PMID 30138131
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  63. PMID 36866171
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  64. S2CID 2344757
    . The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001).
  65. PMID 27141449
    .
  66. PMID 36644692
    . Anabolic–androgenic steroids (AAS) are a class of natural and synthetic hormones that owe their name to their chemical structure (the steroid nucleus, see Figure 1) and the biological effects (anabolic and androgenic) they induce. Anabolic refers to the skeletal muscle-building properties of AAS, whereas androgenic refers to the induction and maintenance of male secondary sexual characteristics (which in principle includes the anabolic action, thereby rendering the term an oxymoron (1)).
  67. PMID 22459616
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  68. S2CID 37898289
    .
  69. PMID 2723028
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  70. PMID 3320548
    . Parenteral routes of sex steroid administration. Liver effects could also be diminished by using routes of administration other than oral. First pass effects would be avoided. [...] Although this discussion has focused predominantly on contraceptives, similar principles seem applicable for diminishing the liver side-effects of androgenic preparations. Thus, androgens should be selected which are likely to be metabolized on entering the hepatocyte and a parenteral route of administration may be preferable. Androgens which are not 17 alkylated might produce fewer liver side-effects than 17 alkylated derivatives judging from their relative effects on plasma protein levels [Z].
  71. PMID 3320549
    . Androgen and oestrogen receptors have been demonstrated in mammalian liver, but since it is generally accepted that they are probably non-functional at endogenous steroid concentrations, it is not apparent how they mediate physiological influences on this organ. Nor is it certain to what extent pharmacological actions of sex hormones reflect overstimulation of physiological routes or whether alternative mechanisms become available once threshold values have been reached. [...] Many of the dangers inherent in synthetic androgen or anabolic steroid therapy may be due less to the androgenic characteristics than to the structural modifications performed to prevent [hepatic] inactivation (e.g. insertion of an acetylene group at 17α).
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    PMID 23027466
    . Both male (androgens) and female (oestrogens, progestins) sex hormones are steroid hormones. [...] these compounds have several properties in common: they are small, very lipophilic molecules with the potential to freely diffuse through cell membranes. Their receptors also share important features: in all animals, the receptors for steroid hormones are part of the nuclear receptor superfamily of ligand-triggered transcription factors (Mangelsdorf et al. 1995). Unlike membrane receptors that trigger intracellular signalling pathways, these receptors work by influencing gene expression in the cell.
  75. ^
    PMID 34218646
    . Intracellular receptors account for 10% to 15% of drugs on the market, including drugs that act on cytoplasmic receptors such as androgen receptors (ARs), estrogen receptors, progesterone receptors, and glucocorticoid receptors, and other drugs that act on nuclear receptors such as vitamin D receptor (VDR), thyroid hormone receptors, and peroxisome proliferator-activated receptors [27-30]. Ligands of intracellular receptors include lipophilic vitamins, steroid hormones, and small chemicals such as hydrogen peroxide and nitric oxide, which require membrane permeability for intracellular delivery [30,31]. There are several barriers to the intracellular delivery of therapeutic drugs, such as lysosome degradation and active efflux out of the cell. Lowmolecular-weight lipophilic compounds can diffuse directly into cells, whereas high-molecular-weight compounds usually need membrane transporters or endocytosis [32,33]. Proper entry into the cell and subsequent contact with the exact target lead to better therapeutic effects and reduce undesirable adverse effects [34].
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    . Bone-sparing effects of antiandrogen monotherapy might be due to selective AR modulators, tissue-specific and androgen-responsive, not affected by antiandrogen therapy, resulting in testosterone still being active in bone during non-steroidal antiandrogen administration [90].
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Further reading

External links
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