Enobosarm: Difference between revisions

{{Short description|Investigational selective androgen receptor modulator}}

{{Redirect|Ostarine|the chemical structure mistakenly linked to the name|Andarine}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| verifiedrevid = 442479761

| IUPAC_name = ((2''S'')-3-(4-cyanophenoxy)-''N''-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide)

| image = Ostarine.svg

| width = 250px

<!--Clinical data-->

| tradename =

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

| pregnancy_category =

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->

| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->

| legal_US = Investigational New Drug

| legal_status =

| routes_of_administration = [[Oral administration|By mouth]]<ref name="pmid32257854" />

<!--Pharmacokinetic data-->

| bioavailability = 100% (rats)<ref name="pmid24074268" />

| protein_bound =

| metabolism = [[CYP3A4]], [[UGT1A1]], [[UGT2B7]]<ref name="pmid27105861" />

| metabolites = Enobosarm glucuronide<ref name="pmid27105861" />

| elimination_half-life = 14–24 hours<ref name="pmid24490605" /><ref name="pmid19852734" /><ref name="pmid27105861" /><ref name="JonesCossSteinerDalton2013" />

| excretion = [[Feces]] (70%), [[urine]] (21–25%) (rats)<ref name="pmid24074268" />

<!--Identifiers-->

| CAS_number = 841205-47-8

| ATC_prefix = None

| ATC_suffix =

| ATC_supplemental =

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = O3571H3R8N

| PubChem = 11326715

| IUPHAR_ligand =

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB12078

| ChemSpiderID = 9501667

| KEGG = D10221

| ChEBI =

| ChEMBL = 1738889

| NIAID_ChemDB =

| PDB_ligand = RLJ

| synonyms = Ostarine; GTx-024; MK-2866; S-22; VERU-024<ref name="AdisInsight">{{cite web|title=Enobosarm - GTx|url=https://adisinsight.springer.com/drugs/800022562| work = Adis Insight | publisher = Springer Nature Switzerland AG |access-date=22 December 2023}}</ref>

<!--Chemical data-->

| C=19 | H=14 | F=3 | N=3 | O=3

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

| StdInChI = 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

| StdInChIKey = JNGVJMBLXIUVRD-SFHVURJKSA-N

<!--Physical data-->

| melting_point = 132

| melting_high = 136

<!-- Definition and medical uses -->

'''Enobosarm''', also formerly known as '''ostarine''' and by the developmental code names '''GTx-024''', '''MK-2866''', and '''S-22''', is a [[selective androgen receptor modulator]] (SARM) which is under development for the treatment of [[hormone sensitive cancer|androgen receptor-positive]] [[breast cancer]] in women and for improvement of [[body composition]] (e.g., prevention of [[muscle loss]]) in people taking [[GLP-1 receptor agonist]]s like [[semaglutide]].<ref name="AdisInsight" /><ref name="pmid24490605">{{cite journal | vauthors = Srinath R, Dobs A | title = Enobosarm (GTx-024, S-22): a potential treatment for cachexia | journal = Future Oncology | volume = 10 | issue = 2 | pages = 187–194 | date = February 2014 | pmid = 24490605 | doi = 10.2217/fon.13.273 | quote = 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]. }}</ref><ref name="JonesCossSteinerDalton2013">{{cite journal | vauthors = Jones A, Coss CC, Steiner MS, Dalton JT | title=An overview on selective androgen receptor modulators: Focus on enobosarm | journal=Drugs of the Future | volume=38 | issue=5 | date=2013 | issn=0377-8282 | doi=10.1358/dof.2013.038.05.1970866 | pages=309–316| s2cid=75202407| url=https://access.portico.org/stable?au=pjbf78xgbrx}}</ref><ref name="pmid36972361">{{cite journal | vauthors = Dai C, Ellisen LW | title = Revisiting Androgen Receptor Signaling in Breast Cancer | journal = The Oncologist | volume = 28 | issue = 5 | pages = 383–391 | date = May 2023 | pmid = 36972361 | pmc = 10166165 | doi = 10.1093/oncolo/oyad049 }}</ref><ref name="Biospace2024" /> It was also under development for a variety of other indications, including treatment of [[cachexia]], [[Duchenne muscular dystrophy]], [[muscle atrophy]] or [[sarcopenia]], and [[stress incontinence|stress urinary incontinence]], but development for all other uses has been discontinued.<ref name="AdisInsight" /><ref name="pmid32476495" /><ref name="pmid32257854" /> Enobosarm was evaluated for the treatment of [[muscle wasting]] related to [[cancer]] in [[Phases of clinical research#Phase III|late-stage]] [[clinical trial]]s, and the drug improved [[lean body mass]] in these trials, but it was not effective in improving [[muscle strength]].<ref name="pmid27535042">{{cite journal | vauthors = Wu C, Kovac JR | title = Novel Uses for the Anabolic Androgenic Steroids Nandrolone and Oxandrolone in the Management of Male Health | journal = Current Urology Reports | volume = 17 | issue = 10 | pages = 72 | date = October 2016 | pmid = 27535042 | doi = 10.1007/s11934-016-0629-8 | quote = 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. | s2cid = 43199715 }}</ref><ref name="pmid32257854" /><ref name="pmid36479151">{{cite journal | vauthors = Mohideen H, Hussain H, Dahiya DS, Wehbe H | title = Selective Androgen Receptor Modulators: An Emerging Liver Toxin | journal = Journal of Clinical and Translational Hepatology | volume = 11 | issue = 1 | pages = 188–196 | date = February 2023 | pmid = 36479151 | pmc = 9647117 | doi = | quote = 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. }}</ref><ref name="pmid32476495">{{cite journal | vauthors = Fonseca GW, Dworatzek E, Ebner N, Von Haehling S | title = Selective androgen receptor modulators (SARMs) as pharmacological treatment for muscle wasting in ongoing clinical trials | journal = Expert Opinion on Investigational Drugs | volume = 29 | issue = 8 | pages = 881–891 | date = August 2020 | pmid = 32476495 | doi = 10.1080/13543784.2020.1777275 | quote = [...] 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]. | s2cid = 219174372 }}</ref><ref name="Businesswire2013">{{cite press release | url=https://www.businesswire.com/news/home/20130819005378/en/GTx-Reports-Results-for-Enobosarm-POWER-Trials-for-the-Prevention-and-Treatment-of-Muscle-Wasting-in-Patients-with-Non-Small-Cell-Lung-Cancer | title=GTX Reports Results for Enobosarm POWER Trials for the Prevention and Treatment of Muscle Wasting in Patients with Non-Small Cell Lung Cancer | date=19 August 2013 }}</ref> As a result, enobosarm was not approved and development for this use was terminated.<ref name="pmid32257854" /> Enobosarm is taken [[oral administration|by mouth]].<ref name="pmid32257854">{{cite journal | vauthors = Christiansen AR, Lipshultz LI, Hotaling JM, Pastuszak AW | title = Selective androgen receptor modulators: the future of androgen therapy? | journal = Translational Andrology and Urology | volume = 9 | issue = Suppl 2 | pages = S135–S148 | date = March 2020 | pmid = 32257854 | pmc = 7108998 | doi = 10.21037/tau.2019.11.02 | quote = 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. | doi-access = free }}</ref>

<!-- Side effects and mechanism of action -->

Known possible [[side effect]]s of enobosarm include [[headache]], [[fatigue (medical)|fatigue]], [[anemia]], [[nausea]], [[diarrhea]], [[back pain]], adverse [[lipid]] changes like decreased [[high-density lipoprotein]] (HDL) [[cholesterol]] levels, changes in [[sex hormone]] concentrations like decreased [[testosterone]] levels, [[elevated liver enzymes]], and [[liver toxicity]], among others.<ref name="pmid19852734">{{cite journal | vauthors = Zilbermint MF, Dobs AS | title = Nonsteroidal selective androgen receptor modulator Ostarine in cancer cachexia | journal = Future Oncology | volume = 5 | issue = 8 | pages = 1211–1220 | date = October 2009 | pmid = 19852734 | doi = 10.2217/fon.09.106 }}</ref><ref name="pmid33672087">{{cite journal | vauthors = Tauchen J, Jurášek M, Huml L, Rimpelová S | title = Medicinal Use of Testosterone and Related Steroids Revisited | journal = Molecules | volume = 26 | issue = 4 | page = 1032 | date = February 2021 | pmid = 33672087 | pmc = 7919692 | doi = 10.3390/molecules26041032 | doi-access = free }}</ref><ref name="pmid30503797">{{cite journal | vauthors = Solomon ZJ, Mirabal JR, Mazur DJ, Kohn TP, Lipshultz LI, Pastuszak AW | title = Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications | journal = Sexual Medicine Reviews | volume = 7 | issue = 1 | pages = 84–94 | date = January 2019 | pmid = 30503797 | pmc = 6326857 | doi = 10.1016/j.sxmr.2018.09.006 }}</ref><ref name="pmid26401842">{{cite journal | vauthors = Choi SM, Lee BM | title = Comparative safety evaluation of selective androgen receptor modulators and anabolic androgenic steroids | journal = Expert Opinion on Drug Safety | volume = 14 | issue = 11 | pages = 1773–1785 | date = 2015 | pmid = 26401842 | doi = 10.1517/14740338.2015.1094052 | quote = 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]. | s2cid = 8104778 }}</ref><ref name="pmid36479151" /> The potential [[virilization|masculinizing]] effects of enobosarm, for instance in women, have largely not been evaluated and are unknown.<ref name="pmid33148520" /> The potential [[adverse effect]]s and risks of high doses of enobosarm are also unknown.<ref name="pmid33148520" /> Enobosarm is a [[nonsteroidal]] SARM, acting as an [[agonist]] of the [[androgen receptor]] (AR), the [[biological target]] of [[androgen]]s and [[anabolic steroid]]s like [[testosterone (medication)|testosterone]] and [[dihydrotestosterone]] (DHT).<ref name="pmid32476495" /> However, it shows dissociation of effect between tissues in [[preclinical research|preclinical studies]], with agonistic and [[anabolic]] effects in muscle and bone, agonistic effects in [[breast]], and [[partial agonist|partially agonistic]] or [[receptor antagonist|antagonistic]] effects in the [[prostate gland]] and [[seminal vesicles]].<ref name="JonesCossSteinerDalton2013" /><ref name="pmid32476495" /><ref name="pmid32257854" /><ref name="MohlerNair2005" /><ref name="pmid25722318">{{cite journal | vauthors = Proverbs-Singh T, Feldman JL, Morris MJ, Autio KA, Traina TA | title = Targeting the androgen receptor in prostate and breast cancer: several new agents in development | journal = Endocrine-Related Cancer | volume = 22 | issue = 3 | pages = R87–R106 | date = June 2015 | pmid = 25722318 | pmc = 4714354 | doi = 10.1530/ERC-14-0543 | quote = 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). }}</ref> The AR-mediated effects of enobosarm in many other androgen-sensitive tissues are unknown.<ref name="MohlerNair2005" /><ref name="pmid25905231" />

<!-- History, society, and culture -->

Enobosarm was first identified in 2004<ref name="pmid27535042" /> and has been under clinical development since at least 2005.<ref name="AdisInsight" /><ref name="MohlerNair2005">{{cite journal | vauthors = Mohler ML, Nair VA, Hwang DJ, Rakov IM, Patil R, Miller DD | title=Nonsteroidal tissue selective androgen receptor modulators: a promising class of clinical candidates | journal=Expert Opinion on Therapeutic Patents | publisher=Informa Healthcare | volume=15 | issue=11 | date=2005-10-28 | issn=1354-3776 | doi=10.1517/13543776.15.11.1565 | pages=1565–1585| s2cid=96279138 }}</ref> It is the most well-studied SARM of all of the agents that have been developed.<ref name="ZajacSeeman2020">{{cite book | vauthors = Zajac JD, Seeman E, Russell N, Ramchand SK, Bretherton I, Grossmann M, Davey RA |title=Encyclopedia of Bone Biology |date=2020 |publisher=Academic Press |isbn=978-0-12-814082-6 |pages=533–550 |chapter=Testosterone|ref={{sfnref|Zajac et al.|2020}}}}</ref> 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{{nbsp}}mg as of 2020.<ref name="pmid32476495" /><ref name="Biospace2016">{{cite web | title = GTx, Inc. Release: Enobosarm Meets Pre-Specified Primary Efficacy Endpoint In Ongoing Phase 2 Clinical Trial In ER+/AR+ Breast Cancer | date = 28 November 2016 | work = BioSpace | url = https://www.biospace.com/article/releases/gtx-inc-release-enobosarm-meets-pre-specified-primary-efficacy-endpoint-in-ongoing-phase-2-clinical-trial-in-er-ar-breast-cancer-/ | quote = 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.}}</ref> However, enobosarm has not yet completed clinical development or been approved for any use.<ref name="AdisInsight" /><ref name="pmid32257854" /> As of November 2023, it is in [[Phases of clinical research#Phase III|phase 3]] [[clinical trial]]s for the treatment of breast cancer and is in [[Phases of clinical research#Phase II|phase 2]] studies for improvement of body composition in people taking GLP-1 receptor agonists.<ref name="AdisInsight" /><ref name="Biospace2024" /> Enobosarm was developed by [[GTx Incorporated|GTx, Inc.]], and is now being developed by Veru, Inc.<ref name="AdisInsight" />

<!-- Non-medical use -->

Aside from its development as a potential [[pharmaceutical drug]], enobosarm is on the [[World Anti-Doping Agency]] [[List of drugs banned by the World Anti-Doping Agency|list of prohibited substances]] and is sold for [[performance-enhancing substance|physique- and performance-enhancing]] purposes by black-market Internet suppliers.<ref name="pmid32476495" /><ref name="pmid33148520" /> In one survey, 2.7% of young male gym users reported using SARMs.<ref name="pmid38059982">{{cite journal | vauthors = Leciejewska N, Jędrejko K, Gómez-Renaud VM, Manríquez-Núñez J, Muszyńska B, Pokrywka A | title = Selective androgen receptor modulator use and related adverse events including drug-induced liver injury: Analysis of suspected cases | journal = European Journal of Clinical Pharmacology | volume = 80| issue = 2| date = December 2023 | pages = 185–202 | pmid = 38059982 | doi = 10.1007/s00228-023-03592-3 | doi-access = free | pmc = 10847181 }}</ref> In addition, a London [[wastewater surveillance|wastewater analysis]] found that enobosarm was the most abundant "pharmaceutical drug" detected and was more prevalent than [[recreational drug]]s like [[MDMA]] and [[cocaine]].<ref name="TheGuardian2018" /> Enobosarm is often used in these contexts at doses greatly exceeding those evaluated in clinical trials, with unknown effectiveness and [[drug safety|safety]].<ref name="pmid33148520" /> Many products sold online that are purported to be enobosarm either contain none or contain other unrelated substances.<ref name="pmid33148520" /><ref name="pmid29183075">{{cite journal | vauthors = Van Wagoner RM, Eichner A, Bhasin S, Deuster PA, Eichner D | title = Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet | journal = JAMA | volume = 318 | issue = 20 | pages = 2004–2010 | date = November 2017 | pmid = 29183075 | pmc = 5820696 | doi = 10.1001/jama.2017.17069 }}</ref> [[Social media]] has played an important role in facilitating the widespread non-medical use of SARMs.<ref name="pmid35574698" />

{{TOC limit|3}}

==Medical uses==

Enobosarm is not approved for any medical use and is not available as a licensed [[pharmaceutical drug]] as of 2023.<ref name="AdisInsight" /><ref name="pmid32257854" /><ref name="pmid32476495" /><ref name="pmid33148520" />

==Side effects==

General [[side effect]]s that have been reported with enobosarm in clinical trials include [[headache]], [[fatigue (medical)|fatigue]], [[anemia]], [[nausea]], [[diarrhea]], and [[back pain]].<ref name="pmid19852734" /><ref name="pmid37571268">{{cite journal | vauthors = Hall E, Vrolijk MF | title = Androgen Receptor and Cardiovascular Disease: A Potential Risk for the Abuse of Supplements Containing Selective Androgen Receptor Modulators | journal = Nutrients | volume = 15 | issue = 15 | page = 3330 | date = July 2023 | pmid = 37571268 | pmc = 10420890 | doi = 10.3390/nu15153330 | quote = 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]. | doi-access = free }}</ref><ref name="pmid33672087" />

Enobosarm has shown [[dose dependence|dose-related]] adverse effects on [[serum lipids]], [[sex hormone]] and [[gonadotropin]] levels, and [[carrier protein]] levels in clinical trials.<ref name="pmid26401842" /><ref name="pmid33148520" /><ref name="pmid22031847" /> It decreases [[HDL cholesterol]] levels, reducing them dose-dependently by 17% at a dose of 1{{nbsp}}mg/day and by 27% at a dose of 3{{nbsp}}mg/day.<ref name="pmid26401842" /><ref name="pmid33148520" /><ref name="pmid22031847" /> Decreases in [[total cholesterol]] levels and in [[triglyceride]] levels have also been seen, whereas [[LDL cholesterol]] levels are unchanged.<ref name="pmid26401842" /><ref name="pmid33148520" /><ref name="pmid22031847" /> In healthy elderly men, total [[testosterone]] levels decreased significantly at doses of 1 and 3{{nbsp}}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{{nbsp}}mg/day.<ref name="pmid26401842" /><ref name="pmid22031847" /> In healthy postmenopausal women, LH and FSH decreased significantly only at the 3{{nbsp}}mg/day dose (-17% and -30%, respectively), whereas levels of total testosterone, free testosterone, DHT, and estradiol did not clearly change relative to placebo.<ref name="pmid26401842" /><ref name="pmid33148520" /><ref name="pmid22031847" /> SHBG levels were lowered at doses of 1 to 3{{nbsp}}mg/day, decreasing dramatically by 61% in men and by 80% in women at the 3{{nbsp}}mg/day dose.<ref name="pmid26401842" /><ref name="pmid33148520" /><ref name="pmid22031847" /> For comparison, [[testosterone enanthate]] by [[intramuscular injection]] at a highly [[:wikt:supraphysiological|supraphysiological]] dose of 600{{nbsp}}mg/week resulted in only a 31% decrease in SHBG levels.<ref name="pmid22031847" /><ref name="pmid8637535">{{cite journal | vauthors = Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R | title = The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men | journal = The New England Journal of Medicine | volume = 335 | issue = 1 | pages = 1–7 | date = July 1996 | pmid = 8637535 | doi = 10.1056/NEJM199607043350101 | doi-access = free }}</ref> Despite the large changes in SHBG levels, levels of free testosterone did not significantly change in either men or women.<ref name="pmid26401842" /><ref name="pmid33148520" /><ref name="pmid22031847" /> Small but significant increases in [[hemoglobin]] and [[hematocrit]], and small but significant decreases in [[blood sugar level|fasting blood glucose]], [[insulin]] levels, and [[insulin resistance]], have been observed with enobosarm at 3{{nbsp}}mg/day.<ref name="pmid33148520" /><ref name="pmid24407183">{{cite journal | vauthors = Coss CC, Jones A, Hancock ML, Steiner MS, Dalton JT | title = Selective androgen receptor modulators for the treatment of late onset male hypogonadism | journal = Asian Journal of Andrology | volume = 16 | issue = 2 | pages = 256–261 | date = 2014 | pmid = 24407183 | pmc = 3955335 | doi = 10.4103/1008-682X.122339 | doi-access = free }}</ref><ref name="pmid22031847" /><ref name="pmid19852734" />

In small short-term (3-month) clinical trials in healthy elderly or postmenopausal women, enobosarm at doses ranging from 0.1 to 3{{nbsp}}mg/day had mixed effects on [[sebum]] production and did not increase [[body hair]] [[hair growth|growth]] or cause [[hirsutism]].<ref name="pmid24945109">{{cite journal | vauthors = Coss CC, Jones A, Dalton JT | title = Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer | journal = Steroids | volume = 90 | issue = | pages = 94–100 | date = November 2014 | pmid = 24945109 | doi = 10.1016/j.steroids.2014.06.010 | s2cid = 23450056 }}</ref><ref name="pmid22031847" /> These effects are measures of androgenic action in [[skin]] and [[hair follicle]]s.<ref name="pmid24945109" /> In the first study, at doses of 0.1 to 3{{nbsp}}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.<ref name="pmid24945109" /><ref name="pmid22031847" /> In the second study, which employed 3{{nbsp}}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.<ref name="pmid24945109" /> No differences in [[sebaceous gland]] volume were apparent upon [[histology|histological]] examination in this study.<ref name="pmid24945109" />

At doses ranging from 0.1 to 18{{nbsp}}mg/day in clinical trials, enobosarm has been associated with [[elevated liver enzymes]] in subsets of individuals.<ref name="pmid36479151" /><ref name="pmid26401842" /> Rates of elevated liver enzymes or of elevated [[alanine aminotransferase]] (ALT) levels have ranged from 0.6% to 33% in these trials.<ref name="pmid36479151" /><ref name="pmid26401842" /> Liver enzyme elevations with enobosarm are often transient and resolve spontaneously.<ref name="pmid36479151" /> However, markedly elevated liver enzymes have occasionally occurred with enobosarm in clinical trials and have necessitated [[drug discontinuation|discontinuation]].<ref name="pmid36479151" /> There have been several published [[case report]]s of [[hepatotoxicity]] with enobosarm as of 2023.<ref name="pmid36479151" /><ref name="pmid37218811">{{cite journal | vauthors = Vignali JD, Pak KC, Beverley HR, DeLuca JP, Downs JW, Kress AT, Sadowski BW, Selig DJ | title = Systematic Review of Safety of Selective Androgen Receptor Modulators in Healthy Adults: Implications for Recreational Users | journal = Journal of Xenobiotics | volume = 13 | issue = 2 | pages = 218–236 | date = May 2023 | pmid = 37218811 | pmc = 10204391 | doi = 10.3390/jox13020017 | doi-access = free }}</ref><ref name="pmid38059982" /><ref name="pmid34368386">{{cite journal | vauthors = Bedi H, Hammond C, Sanders D, Yang HM, Yoshida EM | title = Drug-Induced Liver Injury From Enobosarm (Ostarine), a Selective Androgen Receptor Modulator | journal = ACG Case Reports Journal | volume = 8 | issue = 1 | pages = e00518 | date = January 2021 | pmid = 34368386 | pmc = 8337042 | doi = 10.14309/crj.0000000000000518 }}</ref><ref name="pmid35655632">{{cite journal | vauthors = Weinblatt D, Roy S | title = Drug-Induced Liver Injury Secondary to Enobosarm: A Selective Androgen Receptor Modulator | journal = Journal of Medical Cases | volume = 13 | issue = 5 | pages = 244–248 | date = May 2022 | pmid = 35655632 | pmc = 9119364 | doi = 10.14740/jmc3937 }}</ref><ref name="pmid37871633">{{cite journal | vauthors = Mertens JE, Bömmer MT, Regier MB, Gabriëls G, Pavenstädt H, Grünewald I, Horvath J, Trebicka J, Schmidt H, Schlevogt B | title = Liver Injury after Selective Androgen Receptor Modulator Intake: A Case Report and Review of the Literature | journal = Zeitschrift für Gastroenterologie | volume = | issue = | date = October 2023 | pmid = 37871633 | doi = 10.1055/a-2165-6323 | s2cid = 264426934 }}</ref><ref name="pmid37501938">{{cite journal | vauthors = Arayangkool C, Gozun M, Tanariyakul M, Techasatian W, Leesutipornchai T, Nishimura Y | title = Bile Cast Nephropathy Because of Acute Liver Injury Associated With Selective Androgen Receptor Modulators | journal = ACG Case Reports Journal | volume = 10 | issue = 7 | pages = e01105 | date = July 2023 | pmid = 37501938 | pmc = 10371315 | doi = 10.14309/crj.0000000000001105 }}</ref> Between 2020 and 2022, there has been a rapid increase in reported cases of liver toxicity with SARMs.<ref name="pmid37218811" /> The hepatotoxicity with SARMs may be related to their resistance to [[liver|hepatic]] [[metabolism]], analogously to the case of [[17α-alkylated anabolic steroid]]s.<ref name="pmid36479151" />

SARMs are often advertised and sold on the Internet at doses higher than have been described in the literature.<ref name="pmid33148520" /><ref name="pmid37571268" /> Sometimes doses are recommended as several-fold or more greater than the doses used in clinical trials, or seemingly arbitrary doses are advised.<ref name="pmid33148520" /><ref name="pmid37571268" /> For instance, enobosarm has been provided at doses of greater than or equal to 20{{nbsp}}mg per serving and recommended by bodybuilders and fitness enthusiasts at doses of 10 to 30{{nbsp}}mg/day, relative to the most widely assessed highest dose in clinical trials of 3{{nbsp}}mg/day—an up to 10-fold difference.<ref name="pmid33148520" /><ref name="pmid37571268" /> SARMs, particularly when used at high or excessive doses for prolonged periods of time, may result in substantial suppression of [[endogenous]] [[sex hormone]]s like [[testosterone]] and [[estradiol]], in turn producing widespread unintended deleterious effects on physiological function.<ref name="pmid33148520" /> As examples, SARMs may produce potent anabolic effects with deficiency in important androgenic effects, may result in [[estrogen deficiency]] with consequences like [[osteoporosis|bone loss]] among others, and, due to suppression of the [[hypothalamic–pituitary–gonadal axis]] (HPG axis), may cause [[infertility]].<ref name="pmid33148520" />

[[Androgen]]s and [[anabolic steroid]]s like [[testosterone (medication)|testosterone]], [[dihydrotestosterone]] (DHT), [[nandrolone]], and [[oxandrolone]], which are [[full agonist]]s of the [[androgen receptor]], produce [[virilization|virilizing]] or [[masculinization|masculinizing]] effects like increased sebum production and [[acne]], increased [[body hair]] [[hair growth|growth]], [[scalp hair loss]], [[voice deepening]], increased [[muscle mass]], [[android fat distribution|android fat redistribution]], skeletal changes like [[shoulder broadening|widening of the shoulders]] and skull/facial changes, and [[genital]] growth both in males and females.<ref name="pmid18500378">{{cite journal | vauthors = Kicman AT | title = Pharmacology of anabolic steroids | journal = British Journal of Pharmacology | volume = 154 | issue = 3 | pages = 502–521 | date = June 2008 | pmid = 18500378 | pmc = 2439524 | doi = 10.1038/bjp.2008.165 }}</ref><ref name="Skinner2018">{{cite book | vauthors = Liang JY, Chang HC, Hsu GL | chapter = Penis Endocrinology | veditors = Skinner MK | title=Encyclopedia of Reproduction | publisher=Elsevier Science | year=2018 | isbn=978-0-12-815145-7 | chapter-url=https://books.google.com/books?id=m4RlDwAAQBAJ&pg=PA376 | access-date=23 December 2023 | page=376}}</ref><ref name="pmid33148520">{{cite journal | vauthors = Machek SB, Cardaci TD, Wilburn DT, Willoughby DS | title = Considerations, possible contraindications, and potential mechanisms for deleterious effect in recreational and athletic use of selective androgen receptor modulators (SARMs) in lieu of anabolic androgenic steroids: A narrative review | journal = Steroids | volume = 164 | issue = | pages = 108753 | date = December 2020 | pmid = 33148520 | doi = 10.1016/j.steroids.2020.108753 | quote = 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]. | s2cid = 225049089 }}</ref> SARMs, which are [[tissue selectivity|tissue-selective]] mixed or [[partial agonist]]s of the androgen receptor, are largely uncharacterized in terms of their masculinizing effects, but are likely to produce many of the same effects.<ref name="pmid33148520" /><ref name="pmid18500378" /><ref name="pmid35277356">{{cite journal | vauthors = Handelsman DJ | title = History of androgens and androgen action | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 36 | issue = 4 | pages = 101629 | date = July 2022 | pmid = 35277356 | doi = 10.1016/j.beem.2022.101629 | quote = 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. }}</ref><ref name="pmid21511988">{{cite journal | vauthors = Handelsman DJ | title = Commentary: androgens and "anabolic steroids": the one-headed janus | journal = Endocrinology | volume = 152 | issue = 5 | pages = 1752–1754 | date = May 2011 | pmid = 21511988 | doi = 10.1210/en.2010-1501 | quote = 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. }}</ref> SARMs specifically may be expected to retain masculinizing effects like increased muscle mass and bone changes, while possibly having reduced virilizing effects in certain other areas like androgenic skin and hair changes.<ref name="pmid33148520" /><ref name="pmid26401842" /><ref name="pmid24945109" /><ref name="MohlerNair2005" /><ref name="pmid25905231" /> [[Anecdotal report]]s of masculinization with SARMs in women exist in online forums.<ref name="pmid35574698">{{cite journal | vauthors = Hahamyan HA, Vasireddi N, Voos JE, Calcei JG | title = Social media's impact on widespread SARMs abuse | journal = The Physician and Sportsmedicine | volume = 51 | issue = 4 | pages = 291–293 | date = August 2023 | pmid = 35574698 | doi = 10.1080/00913847.2022.2078679 | doi-access = free }}</ref>

The [[United States]] [[Food and Drug Administration]] (FDA) has cautioned that SARMs could have serious adverse effects ranging from risk of [[heart attack]] to [[stroke]] and [[liver damage]] and has warned against their use in [[bodybuilding]] products.<ref name="FDA2017">{{cite news |title=FDA In Brief: FDA warns against using SARMs in body-building products |url=https://www.fda.gov/news-events/fda-brief/fda-brief-fda-warns-against-using-sarms-body-building-products |access-date=1 August 2019}}</ref>

==Overdose==

Enobosarm has been assessed in clinical trials at doses ranging from 0.1 to 18{{nbsp}}mg/day.<ref name="pmid32476495" /> However, most research has been done at doses of 0.1 to 3{{nbsp}}mg/day, with two [[Phases of clinical research#Phase III|phase 3]] clinical trials using a dosage of 3{{nbsp}}mg/day.<ref name="pmid32257854" /><ref name="pmid30503797" /><ref name="pmid37218811" /><ref name="pmid33148520" /> A few small [[Phases of clinical research#Phase I|phase 1]] and [[Phases of clinical research#Phase II|phase 2]] trials of enobosarm for breast cancer have employed doses of 9 to 18{{nbsp}}mg/day.<ref name="pmid27729416" /><ref name="pmid36479151" /><ref name="pmid32257854" /><ref name="KassemShohdy2019" /> Larger, phase 3 trials of enobosarm at a dose of 9{{nbsp}}mg/day for breast cancer (e.g., ARTEST, n=210) are now underway.<ref name="pmid37946721">{{cite journal | vauthors = Hackbart H, Cui X, Lee JS | title = Androgen receptor in breast cancer and its clinical implication | journal = Translational Breast Cancer Research | volume = 4 | issue = | page = 30 | date = October 2023 | pmid = 37946721 | pmc = 10632549 | doi = 10.21037/tbcr-23-44 | doi-access = free }}</ref><ref name="pmid37684290">{{cite journal | vauthors = Ma J, Chan JJ, Toh CH, Yap YS | title = Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer | journal = npj Breast Cancer | volume = 9 | issue = 1 | pages = 74 | date = September 2023 | pmid = 37684290 | pmc = 10491615 | doi = 10.1038/s41523-023-00578-3 }}</ref> Doses of up to 100{{nbsp}}mg have been assessed in single-dose [[pharmacokinetic]] studies and doses of up to 30{{nbsp}}mg/day have been given in short 14-day pharmacokinetic studies.<ref name="pmid24490605" /> 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{{nbsp}}mg/day), with unknown adverse effects and risks.<ref name="pmid33148520" /><ref name="pmid37571268" />

== Interactions ==

Enobosarm is a [[substrate (biochemistry)|substrate]] of the [[cytochrome P450]] [[enzyme]] [[CYP3A4]] and the [[UDP-glucuronosyltransferase]] (UGT) enzymes [[UGT1A1]] and [[UGT2B7]].<ref name="pmid27105861" /> It shows very minimal [[metabolism]] by cytochrome P50 enzymes, with CYP3A4 merely responsible for the greatest degree of metabolism.<ref name="pmid27105861" /> Since enobosarm is metabolized by CYP3A4, UGT1A1, and UGT2B7, [[enzyme inhibitor|inhibitor]]s and [[enzyme inducer|inducer]]s of these enzymes can modify the metabolism and [[pharmacokinetics]] of enobosarm.<ref name="pmid27105861" /> The strong CYP3A4 inhibitor [[itraconazole]] was shown to have minimal to no influence on the pharmacokinetics of enobosarm, whereas the strong CYP3A4 inducer [[rifampin]] reduced enobosarm [[Cmax (pharmacology)|peak]] levels by 23%, [[elimination half-life]] by 23%, and [[area-under-the-curve levels]] by 43%.<ref name="pmid27885819" /><ref name="pmid27105861" /> The pan-UGT inhibitor [[probenecid]] was shown to not affect peak levels of enobosarm but to increase the elimination half-life of enobosarm by 78% and to increase area-under-the-curve levels of enobosarm by 50%.<ref name="pmid27885819" /><ref name="pmid27105861" /> Enobosarm had no effect on the pharmacokinetics of [[celecoxib]] (a [[CYP2C9]] substrate) or [[rosuvastatin]] (a [[breast cancer resistance protein|BCRP]] substrate).<ref name="pmid27105861" /> Based on the preceding findings, it was concluded that enobosarm poses low risk for clinically relevant [[drug interaction]]s.<ref name="pmid27105861" />

==Pharmacology==

===Pharmacodynamics===

Enobosarm is a [[selective androgen receptor modulator]] (SARM), or a [[tissue selectivity|tissue-selective]] mixed [[agonist]] or [[partial agonist]] of the [[androgen receptor]] (AR).<ref name="pmid25905231" /><ref name="pmid27535042" /><ref name="MohlerNair2005" /> This receptor is the [[biological target]] of [[endogenous]] [[androgen]]s like [[testosterone (medication)|testosterone]] and [[dihydrotestosterone]] (DHT) and of [[synthetic compound|synthetic]] [[anabolic steroid]]s like [[nandrolone]] and [[oxandrolone]].<ref name="pmid27535042" /><ref name="MohlerNair2005" /><ref name="pmid18500378" /> The [[affinity (pharmacology)|affinity]] (K_i) of enobosarm for the AR is high and was measured as 3.8{{nbsp}}nM in one study, or approximately 16.8% of that of DHT.<ref name="pmid23231475" /><ref name="pmid15987833" /><ref name="pmid20444881" /> Enobosarm shows [[enantioselectivity]] for the AR and has similar but somewhat lower [[potency (pharmacology)|potency]] than DHT in terms of activating the receptor.<ref name="JonesCossSteinerDalton2013" /> In addition to general activation of the AR, enobosarm induces the N/C interaction (the interaction of the [[amino terminus]] and [[carboxyl terminus]]) of the AR less potently than does DHT, but in any case promotes the N/C interaction concentration-dependently and to the same maximal extent as DHT.<ref name="pmid20444881" /> The AR is widely expressed in [[tissue (biology)|tissue]]s throughout the body, including in the [[prostate gland]], [[seminal vesicle]]s, [[genital]]s, [[gonad]]s, [[skin]], [[hair follicle]]s, [[muscle]], [[bone]], [[heart]], [[adrenal cortex]], [[liver]], [[kidney]]s, and [[brain]], among others.<ref name="MohlerNair2005" /><ref name="pmid18500378" /> The effects of SARMs including enobosarm in many of these tissues have yet to be characterized.<ref name="MohlerNair2005" /><ref name="pmid25905231" /> In any case, enobosarm has been demonstrated to have varying [[full agonist]] or [[partial agonist]] or [[receptor antagonist|antagonist]] actions in specific tissues, including [[potency (pharmacology)|potent]] agonistic and [[anabolic]] effects in [[muscle]] and [[bone]], potent agonistic effects in AR-expressing human [[breast cancer]] [[cell line]]s like [[MCF-7]] and [[MDA-MB-231]],<ref name="pmid25722318" /><ref name="pmid32257854" /> and partially agonistic or antagonistic effects in the [[prostate gland]], [[seminal vesicle]]s, and [[uterus]].<ref name="JonesCossSteinerDalton2013" /><ref name="pmid32476495" /><ref name="pmid32257854" /><ref name="MohlerNair2005" /><ref name="pmid20444881">{{cite journal | vauthors = Jones A, Hwang DJ, Duke CB, He Y, Siddam A, Miller DD, Dalton JT | title = Nonsteroidal selective androgen receptor modulators enhance female sexual motivation | journal = J Pharmacol Exp Ther | volume = 334 | issue = 2 | pages = 439–48 | date = August 2010 | pmid = 20444881 | pmc = 2913771 | doi = 10.1124/jpet.110.168880 | url = }}</ref> Enobosarm has additionally been shown to stimulate [[sexual motivation]] in female rats similarly to testosterone.<ref name="pmid23231475" /><ref name="pmid20444881" /> Although enobosarm has not been specifically assessed in this area, another structurally unrelated [[quinolinone]] SARM, [[LGD-2226]], has shown [[prosexual]] effects in male rats comparable to those of the synthetic androgen and anabolic steroid [[fluoxymesterone]] as well.<ref name="pmid32257854" /><ref name="pmid23231475" /><ref name="pmid17023534">{{cite journal | vauthors = Miner JN, Chang W, Chapman MS, Finn PD, Hong MH, López FJ, Marschke KB, Rosen J, Schrader W, Turner R, van Oeveren A, Viveros H, Zhi L, Negro-Vilar A | title = An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate | journal = Endocrinology | volume = 148 | issue = 1 | pages = 363–73 | date = January 2007 | pmid = 17023534 | doi = 10.1210/en.2006-0793 | url = }}</ref>

The [[mechanism of action|molecular mechanism]]s underlying the tissue-selective effects of enobosarm and other SARMs compared to testosterone and other androgens and anabolic steroids remain unknown.<ref name="pmid28624515" /><ref name="pmid33148520" /> However, recruitment of both [[coactivator (genetics)|coactivators]] and [[corepressor]]s instead of only coactivators and resultant differing [[protein conformation|receptor conformation]]s, distinct tissue-specific modulation of [[signaling cascade|signaling pathways]] mediating [[nuclear receptor|genomic]] and [[membrane steroid receptor|non-genomic]] effects, and differences in within-tissue [[ligand (biochemistry)|ligand]] [[metabolism]] and modulation of ligand [[potency (pharmacology)|potency]] (i.e., potentiation versus lack thereof), among others, all constitute possible mechanisms.<ref name="pmid28624515" /><ref name="pmid33148520" /><ref name="pmid17339601">{{cite journal | vauthors = Gao W, Dalton JT | title = Ockham's razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase? | journal = Molecular Interventions | volume = 7 | issue = 1 | pages = 10–13 | date = February 2007 | pmid = 17339601 | pmc = 2040232 | doi = 10.1124/mi.7.1.3 }}</ref> In terms of [[transcription coregulator|coregulator]] recruitment, the ratios of coactivators to corepressors vary in different tissues throughout the body, and it is thought that SARMs may have agonistic effects in tissues with an excess of coactivators relative to corepressors like muscle and bone and may have partially agonistic or antagonistic effects in tissues with an excess of corepressors over coactivators like the prostate.<ref name="pmid28624515" /> Another mechanism may be that SARMs like enobosarm induce the N/C interaction less readily than AR full agonists like DHT.<ref name="pmid33148520" /><ref name="pmid23231475" /><ref name="pmid19357508" /><ref name="pmid20444881" /> Induction of the N/C interaction has been associated with the effects of [[endogenous]] and [[exogenous]] AR agonists, for instance [[virilization]] and prostate growth.<ref name="pmid23231475" /><ref name="pmid20444881" /><ref name="HohlMarcelli2023">{{cite book | vauthors = Hohl A, Marcelli M | chapter=Androgen Receptor in Health and Disease | veditors = Hohl A | title=Testosterone | publisher=Springer International Publishing | publication-place=Cham | date=2023 | isbn=978-3-031-31500-8 | doi=10.1007/978-3-031-31501-5_2 | pages=21–75 | chapter-url = https://books.google.com/books?id=GQTOEAAAQBAJ&pg=PA35 | quote = 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].}}</ref><ref name="pmid12051960">{{cite journal | vauthors = He B, Wilson EM | title = The NH(2)-terminal and carboxyl-terminal interaction in the human androgen receptor | journal = Mol Genet Metab | volume = 75 | issue = 4 | pages = 293–8 | date = April 2002 | pmid = 12051960 | doi = 10.1016/S1096-7192(02)00009-4 | url = }}</ref>

In [[animal studies]], enobosarm has shown potent muscle-promoting effects that were similar to those of [[testosterone (medication)|testosterone]] and DHT.<ref name="JonesCossSteinerDalton2013" /><ref name="pmid32476495" /><ref name="pmid24189892">{{cite journal | vauthors = Dalton JT, Taylor RP, Mohler ML, Steiner MS | title = Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer | journal = Current Opinion in Supportive and Palliative Care | volume = 7 | issue = 4 | pages = 345–351 | date = December 2013 | pmid = 24189892 | doi = 10.1097/SPC.0000000000000015 | quote = 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]. | s2cid = 35120033 }}</ref><ref name="pmid26393303">{{cite journal | vauthors = Dubois V, Simitsidellis I, Laurent MR, Jardi F, Saunders PT, Vanderschueren D, Claessens F | title = Enobosarm (GTx-024) Modulates Adult Skeletal Muscle Mass Independently of the Androgen Receptor in the Satellite Cell Lineage | journal = Endocrinology | volume = 156 | issue = 12 | pages = 4522–4533 | date = December 2015 | pmid = 26393303 | doi = 10.1210/en.2015-1479 | doi-access = free | hdl = 20.500.11820/072a494a-dfdc-4785-8f77-1a4e7e40e07a | hdl-access = free }}</ref><ref name="pmid18801930">{{cite journal | vauthors = Narayanan R, Coss CC, Yepuru M, Kearbey JD, Miller DD, Dalton JT | title = Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways | journal = Molecular Endocrinology | volume = 22 | issue = 11 | pages = 2448–2465 | date = November 2008 | pmid = 18801930 | doi = 10.1210/me.2008-0160 | doi-access = free }}</ref><ref name="pmid15987833">{{cite journal | vauthors = Kim J, Wu D, Hwang DJ, Miller DD, Dalton JT | title = The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 315 | issue = 1 | pages = 230–239 | date = October 2005 | pmid = 15987833 | doi = 10.1124/jpet.105.088344 | s2cid = 30799845 }}</ref> 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 [[effective dose (pharmacology)|ED₅₀]] dose for muscle of 0.03{{nbsp}}mg/day.<ref name="pmid24189892" /><ref name="pmid28624515">{{cite journal | vauthors = Narayanan R, Coss CC, Dalton JT | title = Development of selective androgen receptor modulators (SARMs) | journal = Molecular and Cellular Endocrinology | volume = 465 | issue = | pages = 134–142 | date = April 2018 | pmid = 28624515 | pmc = 5896569 | doi = 10.1016/j.mce.2017.06.013 }}</ref><ref name="pmid15987833" /> 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{{nbsp}}mg/day and 0.13{{nbsp}}mg/day, respectively.<ref name="JonesCossSteinerDalton2013" /> 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.<ref name="pmid28624515" /><ref name="pmid15987833" /><ref name="JonesCossSteinerDalton2013" /> 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{{nbsp}}mg/day).<ref name="JonesCossSteinerDalton2013" /> As such, it was more potent in stimulating muscle than testosterone at doses that did not affect [[gonadotropin]] levels.<ref name="pmid24490605" /><ref name="JonesCossSteinerDalton2013" /> 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.<ref name="JonesCossSteinerDalton2013" /> 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.<ref name="JonesCossSteinerDalton2013" /><ref name="pmid35063736">{{cite journal | vauthors = Xie Y, Tian Y, Zhang Y, Zhang Z, Chen R, Li M, Tang J, Bian J, Li Z, Xu X | title = Overview of the development of selective androgen receptor modulators (SARMs) as pharmacological treatment for osteoporosis (1998-2021) | journal = European Journal of Medicinal Chemistry | volume = 230 | issue = | pages = 114119 | date = February 2022 | pmid = 35063736 | doi = 10.1016/j.ejmech.2022.114119 | quote = 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 [...] | s2cid = 245941791 }}</ref><ref name="pmid18801930" /> 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.<ref name="JonesCossSteinerDalton2013" />

In a [[Phases of clinical research#Phase II|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{{nbsp}}mg/day, with a significant 1.3{{nbsp}}kg gain over placebo at 3{{nbsp}}mg/day and a non-significant 0.7{{nbsp}}kg gain over placebo at 1{{nbsp}}mg/day.<ref name="pmid32476495" /><ref name="pmid22031847" /> Similarly, in two [[Phases of clinical research#Phase III|phase 3]] clinical trials in men and postmenopausal women with muscle wasting due to [[non-small-cell lung cancer]], enobosarm at 3{{nbsp}}mg/day significantly increased lean body mass by 0.41{{nbsp}}kg and 0.47{{nbsp}}kg.<ref name="pmid32476495" /> However, enobosarm did not successfully increase muscle strength in these phase 3 trials.<ref name="pmid32476495" /> In any case, it has been suggested that the [[clinical study design|study design]]s and physical function outcomes in such trials may have been flawed.<ref name="pmid28807233">{{cite journal | vauthors = Le-Rademacher JG, Crawford J, Evans WJ, Jatoi A | title = Overcoming obstacles in the design of cancer anorexia/weight loss trials | journal = Critical Reviews in Oncology/Hematology | volume = 117 | issue = | pages = 30–37 | date = September 2017 | pmid = 28807233 | pmc = 5561667 | doi = 10.1016/j.critrevonc.2017.06.008 }}</ref><ref name="pmid33759397">{{cite journal | vauthors = Lambert CP | title = Should the FDA's criteria for the clinical efficacy of cachexia drugs be changed? Is Ostarine safe and effective? | journal = Journal of Cachexia, Sarcopenia and Muscle | volume = 12 | issue = 3 | pages = 531–532 | date = June 2021 | pmid = 33759397 | pmc = 8200429 | doi = 10.1002/jcsm.12695 }}</ref><ref name="pmid30138131">{{cite journal | vauthors = Ramage MI, Skipworth RJ | title = The relationship between muscle mass and function in cancer cachexia: smoke and mirrors? | journal = Current Opinion in Supportive and Palliative Care | volume = 12 | issue = 4 | pages = 439–444 | date = December 2018 | pmid = 30138131 | doi = 10.1097/SPC.0000000000000381 | hdl-access = free | hdl = 20.500.11820/2b90be5b-7682-4681-a85d-101d3abe3ed9 }}</ref><ref name="pmid36866171">{{cite journal | vauthors = Brooks A, Schumpp A, Dawson J, Andriello E, Fairman CM | title = Considerations for designing trials targeting muscle dysfunction in exercise oncology | journal = Frontiers in Physiology | volume = 14 | issue = | pages = 1120223 | date = 2023 | pmid = 36866171 | pmc = 9972098 | doi = 10.3389/fphys.2023.1120223 | doi-access = free }}</ref><ref name="pmid32257854" /> 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{{nbsp}}kg with enobosarm versus 5–8{{nbsp}}kg with 300–600{{nbsp}}mg/week intramuscular testosterone enanthate in healthy young men).<ref name="pmid19357508">{{cite journal | vauthors = Bhasin S, Jasuja R | title = Selective androgen receptor modulators as function promoting therapies | journal = Current Opinion in Clinical Nutrition and Metabolic Care | volume = 12 | issue = 3 | pages = 232–240 | date = May 2009 | pmid = 19357508 | pmc = 2907129 | doi = 10.1097/MCO.0b013e32832a3d79 | quote = 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. }}</ref><ref name="pmid33148520" /><ref name="pmid11701431">{{cite journal | vauthors = Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C, Dzekov J, Bross R, Phillips J, Sinha-Hikim I, Shen R, Storer TW | title = Testosterone dose-response relationships in healthy young men | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 281 | issue = 6 | pages = E1172–E1181 | date = December 2001 | pmid = 11701431 | doi = 10.1152/ajpendo.2001.281.6.E1172 | quote = 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). | s2cid = 2344757 }}</ref> The effects of higher doses of enobosarm (9–18{{nbsp}}mg/day) on lean body mass and muscle strength are also being evaluated in women with breast cancer.<ref name="pmid32257854" /><ref name="KassemShohdy2019">{{cite journal | vauthors = Kassem L, Shohdy KS, Makady NF, Salem DS, Ebrahim N, Eldaly M | title=Efficacy and Safety of Targeting Androgen Receptor in Advanced Breast Cancer: A Systematic Review | journal=Current Cancer Therapy Reviews | volume=15 | issue=3 | date=2019-11-16 | doi=10.2174/1573394714666180821145032 | pages=197–206 | s2cid=58234934 | quote = 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).}}</ref> There is some evidence that women may be more sensitive to lean body mass increases with SARMs, specifically [[GSK2881078|GSK-2881078]] but potentially also others like enobosarm, than men.<ref name="pmid32476495" /><ref name="pmid33148520" />

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.<ref name="pmid18500378" /><ref name="pmid24945109" /><ref name="MohlerNair2005" /><ref name="pmid17339601" /> The [[virilization|virilizing]] and androgenic effects of the traditional steroidal androgens like testosterone in [[skin]], [[hair follicle]]s, and the [[prostate gland]] are attributed to high [[gene expression|expression]] of [[5α-reductase]] in these tissues and consequent local conversion and potentiation into more [[potency (pharmacology)|potent]] androgens.<ref name="pmid18500378" /><ref name="pmid24945109" /><ref name="MohlerNair2005" /> In the case of testosterone, this is via conversion into the 10-fold more potent androgen DHT.<ref name="pmid24945109" /><ref name="MohlerNair2005" /> Enobosarm is not subject to this local transformation and potentiation, and so is theorized to have greatly reduced effects in these tissues relative to testosterone and certain other steroidal androgens.<ref name="pmid24945109" /><ref name="MohlerNair2005" /><ref name="pmid25905231" /> This is likewise theorized to be the case for non-5α-reductase-potentiated anabolic steroids like nandrolone and oxandrolone, which have high [[anabolic steroid#Pharmacology|myotrophic–androgenic potency ratios]] in animals.<ref name="pmid18500378" /> The lack of 5α-reduction may result in reduced androgenic side effects like [[scalp hair loss]], [[hirsutism|facial and body hair growth]], and [[prostatism|prostate growth]].<ref name="pmid25905231" /><ref name="pmid27141449">{{cite journal | vauthors = Pan MM, Kovac JR | title = Beyond testosterone cypionate: evidence behind the use of nandrolone in male health and wellness | journal = Transl Androl Urol | volume = 5 | issue = 2 | pages = 213–9 | date = April 2016 | pmid = 27141449 | pmc = 4837307 | doi = 10.21037/tau.2016.03.03 | doi-access = free | url = }}</ref><ref name="pmid27535042" /> On the other hand, although SARMs, like enobosarm, as well as anabolic steroids, may have reduced virilizing effects in skin and hair follicles, this is not necessarily the case for virilization in general.<ref name="pmid18500378" /><ref name="pmid33148520" /> In particular, the muscle-promoting effects of these agents can be considered a masculinizing effect.<ref name="pmid26401842" /><ref name="pmid36644692">{{cite journal | vauthors = Bond P, Smit DL, de Ronde W | title = Anabolic-androgenic steroids: How do they work and what are the risks? | journal = Frontiers in Endocrinology | volume = 13 | issue = | pages = 1059473 | date = 2022 | pmid = 36644692 | pmc = 9837614 | doi = 10.3389/fendo.2022.1059473 | doi-access = free | quote = 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)). }}</ref> The potential masculinizing effects of enobosarm and SARMs in general are largely uncharacterized and unknown.<ref name="pmid33148520" /> Aside from metabolism differences related to 5α-reduction, enobosarm has also shown much greater impact in the [[liver]], specifically on certain aspects of [[liver protein synthesis|hepatic protein synthesis]] like reduction of [[sex hormone-binding globulin]] (SHBG) production, than even highly [[:wikt:supraphysiological|supraphysiological]] doses of [[parenteral administration|parenteral]] [[testosterone (medication)|testosterone]].<ref name="pmid22031847">{{cite journal | vauthors = Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, Morton RA, Steiner MS | title = 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 = Journal of Cachexia, Sarcopenia and Muscle | volume = 2 | issue = 3 | pages = 153–161 | date = September 2011 | pmid = 22031847 | pmc = 3177038 | doi = 10.1007/s13539-011-0034-6 | quote = 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]. }}</ref> This phenomenon has also been seen with other SARMs, such as [[LGD-4033]],<ref name="pmid33148520" /><ref name="pmid37218811" /><ref name="pmid26401842" /><ref name="pmid22459616">{{cite journal | vauthors = Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R, Ulloor J, Zhang A, Eder R, Zientek H, Gordon G, Kazmi S, Sheffield-Moore M, Bhasin S | title = The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 68 | issue = 1 | pages = 87–95 | date = January 2013 | pmid = 22459616 | pmc = 4111291 | doi = 10.1093/gerona/gls078 }}</ref> as well as with [[synthetic compound|synthetic]] orally active [[17α-alkylated anabolic steroid]]s like [[stanozolol]].<ref name="pmid25905231" /><ref name="pmid3068771">{{cite journal | vauthors = Alén M, Rahkila P | title = Anabolic-androgenic steroid effects on endocrinology and lipid metabolism in athletes | journal = Sports Medicine | volume = 6 | issue = 6 | pages = 327–332 | date = December 1988 | pmid = 3068771 | doi = 10.2165/00007256-198806060-00001 | s2cid = 37898289 }}</ref><ref name="pmid2723028">{{cite journal | vauthors = Sinnecker G, Köhler S | title = Sex hormone-binding globulin response to the anabolic steroid stanozolol: evidence for its suitability as a biological androgen sensitivity test | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 68 | issue = 6 | pages = 1195–1200 | date = June 1989 | pmid = 2723028 | doi = 10.1210/jcem-68-6-1195 }}</ref> It can be attributed to the [[first pass effect|first pass]] through the liver with [[oral administration]] and to the high oral [[bioavailability]] and strong resistance to hepatic metabolism of these agents.<ref name="pmid25905231" /><ref name="pmid3320548">{{cite journal | vauthors = Eisenfeld AJ, Aten RF | title = Estrogen receptors and androgen receptors in the mammalian liver | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 4–6 | pages = 1109–1118 | date = 1987 | pmid = 3320548 | doi = 10.1016/0022-4731(87)90197-x | quote = 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]. }}</ref><ref name="pmid3320549">{{cite journal | vauthors = Lax ER | title = Mechanisms of physiological and pharmacological sex hormone action on the mammalian liver | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 4–6 | pages = 1119–1128 | date = 1987 | pmid = 3320549 | doi = 10.1016/0022-4731(87)90198-1 | quote = 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). }}</ref><ref name="pmid36479151" />

Enobosarm has no [[estrogen (medication)|estrogen]]ic activity, either intrinsic to itself or via its [[metabolite]]s.<ref name="pmid24945109" /><ref name="JonesCossSteinerDalton2013" /><ref name="MohlerNair2005" /><ref name="pmid25905231" /><ref name="pmid27729416">{{cite journal | vauthors = Lim E, Tarulli G, Portman N, Hickey TE, Tilley WD, Palmieri C | title = Pushing estrogen receptor around in breast cancer | journal = Endocrine-Related Cancer | volume = 23 | issue = 12 | pages = T227–T241 | date = December 2016 | pmid = 27729416 | doi = 10.1530/ERC-16-0427 | doi-access = free }}</ref> As a result, the drug is not expected to have [[feminization (biology)|feminizing]] effects or risk of [[gynecomastia]] (breast development) nor to stimulate estrogen-sensitive breast cancer.<ref name="MohlerNair2005" /><ref name="JonesCossSteinerDalton2013" /> 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 [[estrogen]]ic effects in [[bone]] and [[brain]].<ref name="pmid25905231" /> Enobosarm has been found to be a weak [[receptor antagonist|antagonist]] of the [[progesterone receptor]] and hence might have some capacity for [[antiprogestogen]]ic effects.<ref name="pmid24490605" /><ref name="JonesCossSteinerDalton2013" /> Aside from its weak interaction with the progesterone receptor, enobosarm is highly [[binding selectivity|selective]] for the AR and does not bind to other [[nuclear receptor|nuclear hormone receptor]]s.<ref name="JonesCossSteinerDalton2013" />

===Pharmacokinetics===

====Absorption====

Enobosarm is [[oral administration|orally]] [[bioavailability|bioavailable]] due to a lack of extensive [[first-pass metabolism]].<ref name="MohlerNair2005" /> In rats, the oral bioavailability of enobosarm was found to be 100%.<ref name="pmid24074268" /> Enobosarm is rapidly [[absorption (pharmacokinetics)|absorbed]] with oral administration and reaches [[Cmax (pharmacology)|maximal concentration]]s median 1.0{{nbsp}}hours (range 1.0–2.0{{nbsp}}hours) following administration.<ref name="pmid27885819">{{cite journal | vauthors = Thevis M, Kuuranne T, Geyer H, Schänzer W | title = Annual banned-substance review: analytical approaches in human sports drug testing | journal = Drug Testing and Analysis | volume = 9 | issue = 1 | pages = 6–29 | date = January 2017 | pmid = 27885819 | doi = 10.1002/dta.2139 | quote = 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. }}</ref><ref name="pmid24490605" /><ref name="pmid27105861" /> The drug reaches a peak concentration of 56.0{{nbsp}}ng/mL (range 53.1–123.0{{nbsp}}ng/mL) following a single 3{{nbsp}}mg dose and a [[steady state (pharmacology)|steady-state]] peak of 68.1{{nbsp}}ng/mL following repeated 3{{nbsp}}mg doses.<ref name="pmid27885819" /><ref name="pmid27105861" /> The [[pharmacokinetics]] of enobosarm are linear and proportional over a dose range of 1 to 100{{nbsp}}mg in single doses in healthy men.<ref name="pmid24490605" /><ref name="JonesCossSteinerDalton2013" /> The pharmacokinetics of enobosarm are similar in young versus elderly individuals.<ref name="JonesCossSteinerDalton2013" /> A [[:wikt:concentration-time curve|concentration–time curve]] of enobosarm levels following a single oral dose of enobosarm in humans has been published.<ref name="JonesCossSteinerDalton2013" />

====Distribution====

Enobosarm is a [[small-molecule]] and highly [[lipophilicity|lipophilic]] [[chemical compound|compound]].<ref name="PubChem-Enobosarm" /><ref name="DrugBank-Enobosarm" /> Compounds of this type are typically able to diffuse freely through [[biological membrane]]s such as [[cell membrane]]s and barriers like the [[blood–brain barrier]].<ref name="pmid23027466">{{cite book |doi=10.1007/978-3-642-30726-3_24 |chapter=Pharmacology and Clinical Use of Sex Steroid Hormone Receptor Modulators |title=Sex and Gender Differences in Pharmacology |series=Handbook of Experimental Pharmacology |date=2013 | vauthors = Cleve A, Fritzemeier KH, Haendler B, Heinrich N, Möller C, Schwede W, Wintermantel T |volume=214 |issue=214 |pages=543–587 |pmid=23027466 |isbn=978-3-642-30725-6 | quote = 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.}}</ref><ref name="pmid34218646">{{cite journal | vauthors = Yoon JH, Kwon KS | title = Receptor-Mediated Muscle Homeostasis as a Target for Sarcopenia Therapeutics | journal = Endocrinology and Metabolism | volume = 36 | issue = 3 | pages = 478–490 | date = June 2021 | pmid = 34218646 | pmc = 8258343 | doi = 10.3803/EnM.2021.1081 | quote = 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]. }}</ref> This is in fact essential for the action of [[nuclear receptor]] [[ligand (biochemistry)|ligand]]s like enobosarm since their [[biological target]]s (the [[androgen receptor]] in this case) are located [[intracellular]]ly.<ref name="pmid23027466" /><ref name="pmid34218646" /> One ''[[in silico]]'' study predicted that, on the basis of its overall [[physicochemical]] properties (but not considering [[active transport]]), enobosarm would be unlikely to cross the [[blood–brain barrier]] and hence would be a [[peripherally selective drug]] with reduced or no [[central nervous system]] effects.<ref name="pmid23881885">{{cite journal | vauthors = Mohd Fauzi F, Koutsoukas A, Cunningham A, Gallegos A, Sedefov R, Bender A | title = Computer-aided (in silico) approaches in the mode-of-action analysis and safety assessment of ostarine and 4-methylamphetamine | journal = Human Psychopharmacology | volume = 28 | issue = 4 | pages = 365–378 | date = July 2013 | pmid = 23881885 | doi = 10.1002/hup.2322 | s2cid = 22800581 }}</ref> However, in a rat [[tissue distribution]] study, enobosarm was found to be concentrated in [[brain]] tissues to a similar extent as other target tissues like [[skeletal muscle]], [[bone]], [[prostate]], and [[seminal vesicle]]s.<ref name="pmid24074268">{{cite journal | vauthors = Kim J, Wang R, Veverka KA, Dalton JT | title = Absorption, distribution, metabolism and excretion of the novel SARM GTx-024 [(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide] in rats | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 43 | issue = 11 | pages = 993–1009 | date = November 2013 | pmid = 24074268 | doi = 10.3109/00498254.2013.788233 | s2cid = 6545249 }}</ref> This is consistent with enobosarm producing centrally mediated effects in humans like suppression of LH and FSH [[secretion]].<ref name="pmid26401842" /><ref name="pmid33148520" /><ref name="pmid22031847" />

Enobosarm does not bind to [[sex hormone-binding globulin]].<ref name="MohlerNair2005" />

====Metabolism====

''[[In vitro]]'' studies found very minimal [[metabolism]] of enobosarm by human [[cytochrome P450]] [[enzyme]]s.<ref name="pmid27105861">{{cite journal | vauthors = Coss CC, Jones A, Dalton JT | title = Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin | journal = Investigational New Drugs | volume = 34 | issue = 4 | pages = 458–467 | date = August 2016 | pmid = 27105861 | doi = 10.1007/s10637-016-0353-8 | s2cid = 24200291 }}</ref> The greatest degree of [[oxidation|oxidative]] [[metabolite]] generation occurred with [[CYP3A4]].<ref name="pmid27105861" /> Upon incubation with human [[UDP-glucuronosyltransferase]] (UGT) enzymes, enobosarm glucuronide was generated, with a majority of this inactive metabolite being produced by [[UGT1A1]] and [[UGT2B7]].<ref name="pmid27105861" /> Enobosarm glucuronide is the primary circulating metabolite of enobosarm.<ref name="pmid27105861" />

Coadministration of the strong CYP3A4 [[enzyme inhibitor|inhibitor]] [[itraconazole]] had minimal impact on the [[pharmacokinetics]] of enobosarm and enobosarm glucuronide, whereas the strong CYP3A4 [[enzyme inducer|inducer]] [[rifampin]] reduced enobosarm peak levels by 23%, [[elimination half-life]] by 23%, and [[area-under-the-curve levels]] by 43%.<ref name="pmid27885819" /><ref name="pmid27105861" /> Coadministration of the pan-UGT inhibitor [[probenecid]] with enobosarm resulted in similar peak levels of enobosarm but the elimination half-life of enobosarm was extended by 78% and area-under-the-curve levels increased by 50%.<ref name="pmid27885819" /><ref name="pmid27105861" /> These data are consistent with the preclinical findings that enobosarm is a [[substrate (biochemistry)|substrate]] of CYP3A4 and UGT enzymes.<ref name="pmid27105861" />

The metabolism of enobosarm is similar to that of the closely structurally related drug [[bicalutamide]].<ref name="pmid24074268" />

====Elimination====

In rats, enobosarm was [[excretion|excreted]] approximately 70% in [[feces]] and 21 to 25% in [[urine]].<ref name="pmid24074268" />

Enobosarm has an [[elimination half-life]] of approximately 14 to 24{{nbsp}}hours in human volunteers.<ref name="pmid24490605" /><ref name="pmid19852734" /><ref name="JonesCossSteinerDalton2013" /> In one pharmacokinetic study, the mean [[terminal half-life]] was 22.0 ± 5.8 ([[standard deviation|SD]]) hours, with a range of 13.7 to 31.3{{nbsp}}hours in different individuals<ref name="pmid27105861" />

==Chemistry==

Enobosarm is a [[small-molecule]] ([[molecular weight]] = 389.3{{nbsp}}g/mol) and highly [[lipophilicity|lipophilic]] ([[Partition coefficient#Prediction|predicted]] [[Partition coefficient#Partition coefficient and log P|log P]] = 2.7–3.3) [[chemical compound|compound]].<ref name="PubChem-Enobosarm">{{cite web | url=https://pubchem.ncbi.nlm.nih.gov/compound/Enobosarm | title=Enobosarm | work = PubChem | publisher = U.S. National Library of Medicine }}</ref><ref name="DrugBank-Enobosarm">{{cite web | url=https://go.drugbank.com/drugs/DB12078 | title=Enobosarm | work = DrugBank }}</ref>

Enobosarm and related SARMs like [[acetothiolutamide]] and [[andarine]] (acetamidoxolutamide; GTx-007; S-4) were [[chemical derivative|derived]] from [[structural modification]] of the arylpropionamide [[nonsteroidal antiandrogen]] [[bicalutamide]].<ref name="pmid16159155">{{cite journal | vauthors = Gao W, Bohl CE, Dalton JT | title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–3370 | date = September 2005 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u }}</ref><ref name="MohlerNair2005" /><ref name="pmid15994457">{{cite journal | vauthors = Chen J, Kim J, Dalton JT | title = Discovery and therapeutic promise of selective androgen receptor modulators | journal = Molecular Interventions | volume = 5 | issue = 3 | pages = 173–188 | date = June 2005 | pmid = 15994457 | pmc = 2072877 | doi = 10.1124/mi.5.3.7 }}</ref><ref name="pmid25905231">{{cite book | chapter = Androgen Physiology, Pharmacology, Use and Misuse | title = Endotext [Internet] | location = South Dartmouth (MA) | publisher = MDText.com, Inc. | date = 5 October 2020 | pmid = 25905231 | doi = | vauthors = Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, Handelsman DJ }}</ref><ref name="pmid30525603">{{cite journal | vauthors = Hwang DJ, He Y, Ponnusamy S, Mohler ML, Thiyagarajan T, McEwan IJ, Narayanan R, Miller DD | title = New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity | journal = Journal of Medicinal Chemistry | volume = 62 | issue = 2 | pages = 491–511 | date = January 2019 | pmid = 30525603 | doi = 10.1021/acs.jmedchem.8b00973 | hdl-access = free | s2cid = 54472127 | hdl = 2164/13357 }}</ref> They are nonsteroidal arylpropionamides themselves and are close [[structural analogue]]s of bicalutamide.<ref name="MohlerNair2005" /><ref name="pmid15994457" /><ref name="pmid30525603" /><ref name="pmid22612692">{{cite journal | vauthors = Corona G, Rastrelli G, Vignozzi L, Maggi M | title = Emerging medication for the treatment of male hypogonadism | journal = Expert Opinion on Emerging Drugs | volume = 17 | issue = 2 | pages = 239–259 | date = June 2012 | pmid = 22612692 | doi = 10.1517/14728214.2012.683411 | s2cid = 22068249 }}</ref> 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.<ref name="Holderbaum2020">{{cite thesis | vauthors = Holderbaum A | date = April 2020 | degree = Ph.D. | title = Emerging anabolic drugs: investigation of the in vitro and in vivo metabolism of selective androgen receptor modulators. | publisher = Queen's University Belfast | location = United Kingdom | url = https://pureadmin.qub.ac.uk/ws/portalfiles/portal/203231700/thesis_final_submitted_accepted_tracked_changes_Redacted.pdf }}</ref> 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.<ref name="pmid25270521">{{cite journal | vauthors = Ricci F, Buzzatti G, Rubagotti A, Boccardo F | title = Safety of antiandrogen therapy for treating prostate cancer | journal = Expert Opinion on Drug Safety | volume = 13 | issue = 11 | pages = 1483–1499 | date = November 2014 | pmid = 25270521 | doi = 10.1517/14740338.2014.966686 | quote = 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]. | s2cid = 207488100 }}</ref><ref name="pmid17049844">{{cite journal | vauthors = Allan G, Lai MT, Sbriscia T, Linton O, Haynes-Johnson D, Bhattacharjee S, Dodds R, Fiordeliso J, Lanter J, Sui Z, Lundeen S | title = A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 103 | issue = 1 | pages = 76–83 | date = January 2007 | pmid = 17049844 | doi = 10.1016/j.jsbmb.2006.07.006 | s2cid = 25283876 }}</ref><ref name="pmid20950306">{{cite journal | vauthors = Wadhwa VK, Weston R, Parr NJ | title = Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer | journal = BJU International | volume = 107 | issue = 12 | pages = 1923–1929 | date = June 2011 | pmid = 20950306 | doi = 10.1111/j.1464-410X.2010.09726.x | s2cid = 205543615 }}</ref>

Enobosarm (S-22) and andarine (S-4) and their [[chemical structure]]s have sometimes been confused.<ref name="pmid19432422">{{cite journal | vauthors = Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, Hwang DJ, Dalton JT, Miller DD | title = Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 12 | pages = 3597–3617 | date = June 2009 | pmid = 19432422 | doi = 10.1021/jm900280m | quote = Readers are cautioned to note that the name Ostarine is often mistakenly linked to the chemical structure of 8, which is also known as andarine. The chemical structure of Ostarine has not been publicly disclosed. The authors are unable to provide additional information. }}</ref> The chemical structure of enobosarm was not disclosed until November 2011.<ref name="pmid23231475">{{cite journal | vauthors = Zhang X, Sui Z | title = Deciphering the selective androgen receptor modulators paradigm | journal = Expert Opinion on Drug Discovery | volume = 8 | issue = 2 | pages = 191–218 | date = February 2013 | pmid = 23231475 | doi = 10.1517/17460441.2013.741582 | quote = 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). | s2cid = 2584722 }}</ref><ref name="pmid19432422" />

Novel nonsteroidal antiandrogens have been developed from enobosarm with enhanced [[potency (pharmacology)|potency]] and activity relative to conventional antiandrogens like bicalutamide and [[enzalutamide]].<ref name="pmid29895558">{{cite journal | vauthors = Dart DA, Kandil S, Tommasini-Ghelfi S, Serrano de Almeida G, Bevan CL, Jiang W, Westwell AD | title = Novel Trifluoromethylated Enobosarm Analogues with Potent Antiandrogenic Activity ''In Vitro'' and Tissue Selectivity ''In Vivo'' | journal = Molecular Cancer Therapeutics | volume = 17 | issue = 9 | pages = 1846–1858 | date = September 2018 | pmid = 29895558 | doi = 10.1158/1535-7163.MCT-18-0037 | doi-access = free }}</ref><ref name="pmid31288149">{{cite journal | vauthors = Pertusati F, Ferla S, Bassetto M, Brancale A, Khandil S, Westwell AD, McGuigan C | title = A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF₅) and pentafluoroethyl (C₂F₅) substituents: Improved antiproliferative agents against prostate cancer | journal = European Journal of Medicinal Chemistry | volume = 180 | issue = | pages = 1–14 | date = October 2019 | pmid = 31288149 | doi = 10.1016/j.ejmech.2019.07.001 | s2cid = 195872311 | url = https://orca.cardiff.ac.uk/id/eprint/124785/ }}</ref>

==History==

The first SARMs were arylpropionamides derived from the [[nonsteroidal antiandrogen]] [[bicalutamide]].<ref name="JonesCossSteinerDalton2013" /><ref name="pmid9514878">{{cite journal | vauthors = Dalton JT, Mukherjee A, Zhu Z, Kirkovsky L, Miller DD | title = Discovery of nonsteroidal androgens | journal = Biochemical and Biophysical Research Communications | volume = 244 | issue = 1 | pages = 1–4 | date = March 1998 | pmid = 9514878 | doi = 10.1006/bbrc.1998.8209 }}</ref> They were discovered by [[James T. Dalton]] and colleagues at the [[University of Tennessee]] and other institutions and were first described in a paper published in 1998.<ref name="JonesCossSteinerDalton2013" /><ref name="pmid9514878" /><ref name="WO2005120483">{{cite patent | country = WO | number = 2005120483 | inventor = Dalton JT, Mille DD, Veverka KA | assign1 = University of Tennessee Research Foundation | pubdate = 22 December 2005 | url= https://patents.google.com/patent/WO2005120483A2/eninventor=dalton+james+t&before=priority:20041231&after=priority:20040101&oq=dalton+james+t+2004 |title = Selective androgen receptor modulators and methods of use thereof}}</ref> At the time, these AR agonists were referred to as "nonsteroidal androgens", a drug class that had not been previously described.<ref name="pmid10522980">{{cite journal | vauthors = Negro-Vilar A | title = Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 84 | issue = 10 | pages = 3459–3462 | date = October 1999 | pmid = 10522980 | doi = 10.1210/jcem.84.10.6122 }}</ref> By 1999 however, on the basis of the [[selective estrogen receptor modulator]] (SERM)-like [[partial agonist|mixed agonist–antagonist]] and [[tissue selectivity|tissue-selective]] activity of these nonsteroidal AR agonists, the term "selective androgen receptor modulator" or "SARM" was introduced and adoption of this name had begun.<ref name="pmid10522980" /> The arylpropionamide SARM [[andarine]] (GTx-007; S-4) was first described in the literature by 2002.<ref name="pmid12161060">{{cite journal | vauthors = He Y, Yin D, Perera M, Kirkovsky L, Stourman N, Li W, Dalton JT, Miller DD | title = Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor | journal = European Journal of Medicinal Chemistry | volume = 37 | issue = 8 | pages = 619–634 | date = August 2002 | pmid = 12161060 | doi = 10.1016/s0223-5234(02)01335-1 }}</ref><ref name="pmid12604714">{{cite journal | vauthors = Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT | title = Pharmacodynamics of selective androgen receptor modulators | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 304 | issue = 3 | pages = 1334–1340 | date = March 2003 | pmid = 12604714 | doi = 10.1124/jpet.102.040840 | s2cid = 14724811 }}</ref><ref name="Perera2003">{{cite thesis | vauthors = Perera MA |title=The pharmacology, pharmacokinetics and metabolism of a novel nonsteroidal selective androgen receptor modulator |date=2003 |url=http://rave.ohiolink.edu/etdc/view?acc_num=osu1070476461 |id={{ProQuest|305301414}} |oclc=56700020 }}{{page needed|date=January 2024}}</ref> In 2003, arylpropionamide AR agonists, including andarine, were first reported to possess SARM-type [[tissue selectivity]] ''[[in vivo]]''.<ref name="pmid23231475" /><ref name="pmid12604714" /> Enobosarm (GTx-024; S-22), another arylpropionamide SARM, was first identified in 2004<ref name="pmid27535042" /><ref name="WO2005120483" /> and was first described in the literature in 2005.<ref name="MohlerNair2005" /><ref name="pmid15987833" /><ref name="WO2005120483" /> [[GTx Incorporated|GTx]], a [[pharmaceutical company]] founded in [[Memphis, Tennessee]] in 1997, licensed the rights to enobosarm from the University of Tennessee Research Foundation and began developing it as a [[pharmaceutical drug]].<ref name="AdisInsight" /><ref name="WO2005120483" />

A [[Phases of clinical research#Phase I|phase 1]] [[clinical trial]] employing enobosarm had been completed by 2005.<ref name="MohlerNair2005" /> By 2007, enobosarm was in a [[Phases of clinical research#Phase II|phase 2]] trial, and that year GTx signed an exclusive license agreement for its SARM program with [[Merck & Co.]]<ref name="OutsourcingPharma2007">{{cite news | vauthors = Nagle M |title=Merck flexes muscle with GTx deal|url=https://www.outsourcing-pharma.com/Article/2007/11/07/Merck-flexes-muscle-with-GTx-deal|work=Outsourcing Pharma|date=7 November 2007}}</ref> The companies ended the deal in 2010.<ref name="Forbes2010">{{cite news | vauthors = Swanekamp K |title=Merck And GTx Go Their Separate Ways|url=https://www.forbes.com/2010/03/15/gtx-merck-pharma-markets-equities-drug-trial.html#14c838625e4b|work=Forbes|date=15 March 2010}}</ref> In August 2011, there was a 12-week [[randomized controlled trial|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.<ref name="pmid22031847" /> In August 2013, GTx announced that enobosarm had failed in two [[Phases of clinical research#Phase III|phase 3]] clinical trials to treat wasting in people with [[lung cancer]].<ref name="PharmaLetter2013">{{cite news|title=Enobosarm fails endpoints in Ph III study|url=https://www.thepharmaletter.com/article/enobosarm-fails-endpoints-in-ph-iii-study|work=The Pharma Letter|date=20 August 2013}}</ref> The company had invested around $35 million in the development of the drug.<ref name="MBJ2014">{{cite news | vauthors = Sheffield M |title=Steiner resigns from GTx|url=https://www.bizjournals.com/memphis/news/2014/04/04/steiner-resigns-from-gtx.html|work=Memphis Business Journal|date=April 4, 2014}}</ref> 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]].<ref name="FierceBiotech2014">{{cite news | vauthors = Garde D |title=GTx's CEO finds the door as the company moves on from a PhIII failure |url=https://www.fiercebiotech.com/financials/gtx-s-ceo-finds-door-as-company-moves-on-from-a-phiii-failure|work=FierceBiotech|date=4 April 2014}}</ref> As of 2018, enobosarm was the only SARM to have reached or completed phase 3 clinical trials.<ref name="pmid28624515" />

In 2016, GTx began phase 2 trials, to see if enobosarm might be effective to treat [[stress incontinence|stress urinary incontinence]] in women.<ref name="DrugDevTech2016">{{cite news|title=GTx begins Phase II trial of enobosarm to treat women with stress urinary incontinence |url=https://www.drugdevelopment-technology.com/news/newsgtx-begins-phase-ii-trial-of-enobosarm-to-treat-women-with-stress-urinary-incontinence-4785216/ | archive-url = https://web.archive.org/web/20180622164656if_/https://www.drugdevelopment-technology.com/news/newsgtx-begins-phase-ii-trial-of-enobosarm-to-treat-women-with-stress-urinary-incontinence-4785216/ | archive-date = 22 June 2018 |work=Drug Development Technology|date=14 January 2016}}</ref> In 2018, GTx announced the phase 2 trials on the effectiveness of enobosarm for stress urinary incontinence in women failed to achieve its primary endpoint in the ASTRID Trial.<ref name="GEN2018">{{cite news |title=GTx's Enobosarm Fails Phase II Trial in Stress Urinary Incontinence; Stock Plunges 90%+ |url=https://www.genengnews.com/news/gtxs-enobosarm-fails-phase-ii-trial-in-stress-urinary-incontinence-stock-plunges-90/ | work = Genetic Engineering & Biotechnology News | date = 21 September 2018 |access-date=1 August 2019}}</ref> By September 2023, development of enobosarm for stress urinary incontinence had been discontinued.<ref name="AdisInsight" /> In 2022, the FDA granted [[Fast track (FDA)|fast tract designation]] to enobosarm in [[androgen receptor|AR+]], [[estrogen receptor|ER]]+, [[HER2]]- [[metastatic]] [[breast cancer]].<ref name="CancerNetwork2022">{{cite web | vauthors = Pelosci A | date = 10 January 2022 |title=FDA Grants Fast Track Designation to Enobosarm in AR+, ER+, HER2- Metastatic Breast Cancer |url=https://www.cancernetwork.com/view/fda-grants-fast-track-designation-to-enobosarm-in-ar-er-her2--metastatic-breast-cancer |website=Cancer Network |access-date=27 August 2023 |language=en }}</ref> 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 [[GLP-1 receptor agonist|glucagon-like peptide-1 (GLP-1) receptor agonist]]s like [[semaglutide]] for [[weight loss]].<ref name="Biospace2024">{{cite web | title = 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 | date = 8 January 2024 | work = BioSpace | url = https://www.biospace.com/article/releases/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/ }}</ref> In addition, they announced plans to conduct a phase 2b study of enobosarm at doses of 3 to 6{{nbsp}}mg/day for this purpose in sarcopenic obese or overweight elderly individuals receiving GLP-1 receptor agonists.<ref name="Biospace2024" />

Enobosarm was developed by GTx, Inc., and is now being developed by Veru, Inc.<ref name="AdisInsight" />

==Society and culture==

===Names===

Enobosarm is the [[generic term|generic name]] of the drug and its [[International Nonproprietary Name]] (INN).<ref name="WHO2013">{{cite journal | journal = WHO Drug Information | volume = 27 | issue = 1 | date = 2013 | title = Recommended INN: List 69 International Nonproprietary Names for Pharmaceutical Substances (INN) | url = https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/rl69.pdf | quote = Enobosarm: (2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide }}</ref> 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.<ref name="AdisInsight" /><ref name="pmid19852734" /> Enobosarm is also known by the pharmaceutical developmental code names S-22 (synthesis paper), GTx-024 (GTx, Inc.), MK-2866 ([[Merck & Co.|Merck]]), and VERU-024 (Veru, Inc.).<ref name="AdisInsight" />

===Non-medical use===

Enobosarm and other SARMs are sold by black-market vendors on the Internet.<ref name="pmid33148520" /><ref name="pmid29183075" /> These agents have increasingly become used by the general public as "gym supplements" such as [[pre-workout]] or [[lifestyle drug]]s, rather than as an aid to performance in athletic or bodybuilding competitions. In one survey, 2.7% of young male gym users in the [[Netherlands]] reported using SARMs.<ref name="pmid38059982" /> In addition, a 2018 analysis of a [[fatberg]] from a sewer in central [[London]] showed enobosarm to be the most abundant "pharmaceutical drug" detected, and was present at higher concentration than [[recreational drug]]s such as [[MDMA]] and [[cocaine]]. While this isolated result may not be representative of overall levels of use, for enobosarm to be detectable in sewer deposits reflects significant levels of enobosarm use in the area close to where the sample was collected.<ref name="TheGuardian2018">{{cite web | url = https://www.theguardian.com/environment/2018/apr/24/why-there-are-more-gym-supplements-in-a-london-fatberg-than-cocaine-and-mdma | vauthors = Saner E | title = Why there are more gym supplements in a London fatberg than cocaine and MDMA. | work = The Guardian | date = 24 April 2018 }}</ref> Doses of enobosarm sold online and used non-medically are often many times higher than those assessed in clinical trials.<ref name="pmid33148520" /><ref name="pmid37571268" /> Aside from enobosarm, the other most commonly used SARMs include [[vosilasarm]] (RAD140; "testolone"), [[LGD-4033]] (VK5211; "ligandrol"), and [[andarine]] (GTx-007; S-4).<ref name="pmid35574698" /> 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.<ref name="pmid33148520" /><ref name="pmid29183075" /> [[Social media]] has played an important role in facilitating the widespread non-medical use of SARMs.<ref name="pmid35574698" />

===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 [[anabolic steroid]]s. 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.<ref>{{cite journal | vauthors = Thevis M, Kohler M, Schlörer N, Kamber M, Kühn A, Linscheid MW, Schänzer W | title = Mass spectrometry of hydantoin-derived selective androgen receptor modulators | journal = Journal of Mass Spectrometry | volume = 43 | issue = 5 | pages = 639–650 | date = May 2008 | pmid = 18095383 | doi = 10.1002/jms.1364 | bibcode = 2008JMSp...43..639T }}</ref><ref>{{cite journal | vauthors = Thevis M, Kohler M, Thomas A, Maurer J, Schlörer N, Kamber M, Schänzer W | title = Determination of benzimidazole- and bicyclic hydantoin-derived selective androgen receptor antagonists and agonists in human urine using LC-MS/MS | journal = Analytical and Bioanalytical Chemistry | volume = 391 | issue = 1 | pages = 251–261 | date = May 2008 | pmid = 18270691 | doi = 10.1007/s00216-008-1882-6 | s2cid = 206899531 }}</ref> There are a variety of known cases of [[doping in sports]] with enobosarm by [[professional sports|professional]] [[athlete]]s.

====List of doping cases====

{{Further|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]].<ref>{{cite news |title=Dynamic Technical Formulations, LLC. Issues a Voluntary Nationwide Recall of Tri-Ton Due to the Presence of Andarine and Ostarine |url=https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/dynamic-technical-formulations-llc-issues-voluntary-nationwide-recall-tri-ton-due-presence-andarine |agency=U.S. Food & Drug Administration |date=May 19, 2017}}</ref>

In October 2018, [[Ultimate Fighting Championship|UFC]] fighter [[Sean O'Malley (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&nbsp;ng/ml.<ref>{{cite web|url=https://www.espn.com/mma/story/_/id/28538560/nsac-sean-omalley-fight-ufc-248-march-serving-suspension|title=NSAC: Sean O'Malley can fight at UFC 248 in March after serving suspension| vauthors = Raimondi M |publisher=[[ESPN]]|date=January 22, 2020|access-date=June 9, 2020}}</ref>

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 {{nowrap|suspended{{tsp}}{{mdash}}}}{{tsp}}Dexter Lawrence, Braden Galloway and Zach {{nowrap|Giellaall{{tsp}}{{mdash}}}}{{tsp}}tested positive for a substance known as enobosarm. On June 23, 2019 Clemson did not release enobosarm investigation findings, citing privacy law.<ref>{{Cite web | vauthors = Needelman J | date = 14 September 2020 |url= https://www.postandcourier.com/sports/clemson/clemson-lineman-suspended-by-ncaa-for-positive-ostarine-test-opens-up-for-first-time/article_184d6f34-0d8a-11ea-a39b-2bbc07679774.html |title= Clemson lineman suspended by ncaa for positive ostarine test opens up for first time |access-date=November 13, 2020}}</ref>

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.<ref>{{cite news | vauthors = Bieler D |title=Failed PED test has a highly paid offensive lineman sharing polygraph results |url=https://www.washingtonpost.com/sports/2019/07/25/failed-ped-test-has-highly-paid-offensive-lineman-sharing-polygraph-results/ |access-date=25 July 2019 |newspaper=Washington Post |date=25 July 2019 |quote=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.}}</ref>

On October{{spaces}}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{{ndash}}16 October 2020.<ref>{{cite press release |title=UCI statement concerning Matteo Spreafico |url=https://www.uci.org/pressrelease/uci-statement-concerning-matteo-spreafico/G5veDCObgzfby5DEThmjX |publisher=Union Cycliste Internationale |date=4 May 2021 }}</ref>

On July{{spaces}}6, 2021, during the [[2020 Summer Olympics]], [[Brazil women's national volleyball team]] player [[Tandara Caixeta|Tandara]] was temporarily suspended for testing positive for enobosarm. The test was carried out and identified by the Brazilian Doping Control Authority (ABDC).<ref>{{Cite web | url = https://ge.globo.com/olimpiadas/noticia/tandara-e-pega-no-exame-antidoping-e-esta-fora-das-olimpiadas.ghtml |title = Tandara é suspensa por "potencial violação" do antidoping e está fora das Olimpíadas | trans-title = Tandara is suspended for “potential anti-doping violation” and is out of the Olympics | language = Portuguese | date = 6 August 2021 | work = globo.com }}</ref>

On August{{spaces}}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 (drug)|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.<ref>{{Cite web|url=https://news.sky.com/story/tokyo-olympics-team-gb-4x100m-relay-silver-medallist-cj-ujah-suspended-for-suspected-doping-violation-12379886|title = Tokyo Olympics: Team GB 4x100m relay silver medallist CJ Ujah suspended for suspected doping violation | date = 12 August 2021 | work = Sky News }}</ref> Finally in February 2022, Great Britain were stripped of their silver medal.<ref>{{Cite web|url=https://www.bbc.com/sport/athletics/60437373 |title=CJ Ujah: Great Britain lose Tokyo Olympics relay medal after doping violation |publisher=BBC |date=18 February 2022}}</ref> In October 2022, Ujah was suspended for 22 months by the ITA.<ref>{{Cite web |url= https://www.athleticsintegrity.org/downloads/pdfs/disciplinary-process/en/AIU-21-141-UJAH-Communication-CRA_FINAL_updated.pdf |title=Public Disclosure of Disposition of Anti-Doping Matter Under Rule 14.3.2 – Chijindu Ujah (GBR) |publisher=Athletics Integrity Unit |date=10 October 2022 |orig-date=29 September 2022}}</ref>

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.<ref>{{cite web|url=https://woodbine.com/wp-content/uploads/pdfs/Thoroughbred/ORC_Rulings/TB%201732934,%20GERL,%20Robert%20-%20ARAFAT,%20KOMUNIST.pdf |title=In the Matter of the Horse Racing License Act, 2015, S.0.2015,C.38,Sched.9; And in the Matter of Robert Gerl|access-date=2 June 2022}}</ref>

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.<ref>{{cite web|url=https://www.nfl.com/news/cardinals-wr-deandre-hopkins-still-hopes-to-reduce-six-game-suspension |title=Cardinals WR DeAndre Hopkins still hopes to reduce six-game suspension |work=NFL.com |date=23 June 2022}}</ref>

In April 2023, British boxer [[Amir Khan (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.<ref>{{cite web|url=https://www.bbc.co.uk/sport/boxing/65173545 |title= Amir Khan banned for two years after anti-doping test reveals presence of prohibited substance |work=BBC.co.uk |date=4 April 2023}}</ref>

On May 1, 2024, American boxer [[Ryan Garcia]] tested positive for the performance-enhancing substance Ostarine the day before and the day of his upset win over Devin Haney last month, per a Voluntary Anti-Doping Association letter sent to all parties Wednesday and obtained by ESPN. The samples were taken prior to the fight, but the results weren't known until later. Garcia's A-sample also screened positive for 19-norandrosterone, but its presence is unconfirmed at this time. Garcia floored Haney three times during the majority decision victory, but that result could possibly be overturned because his B-sample tested positive on May 22, 2024. Garcia's fate now rests in the hands of the New York State Athletic Commission, which will adjudicate any suspensions and financial penalties. Sanctions also include the possibility of his win over Haney being overturned to a no-contest or having it changed to a disqualification. Despite his "B" samples returning positive results, Garcia has maintained his innocence and has cited substance contamination.<ref name="Coppinger2024">{{cite web | last=Coppinger | first=Mike | title=Boxer Garcia tests positive for banned substance | website=ESPN.com | date=2 May 2024 | url=https://www.espn.com/boxing/story/_/id/40066162/boxer-ryan-garcia-tested-positive-banned-substance-ostarine | access-date=17 August 2024}}</ref>

==Research==

Enobosarm is currently under development for the treatment of [[breast cancer]].<ref name="AdisInsight" /><ref name="pmid36972361" /><ref name="pmid37946721" /><ref name="pmid37684290" /> 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]].<ref name="AdisInsight" /><ref name="pmid32476495" /><ref name="pmid32257854" /> However, development for all other indications has been discontinued.<ref name="AdisInsight" />

Enobosarm was assessed for the treatment of [[muscle wasting]] in people with [[lung cancer]] in two [[Phases of clinical research#Phase III|phase 3]] [[clinical trial]]s.<ref name="pmid27535042" /><ref name="pmid32257854" /><ref name="pmid36479151" /><ref name="Businesswire2013" /> The findings of these trials were reported in 2013.<ref name="Businesswire2013" /> Enobosarm significantly improved [[lean body mass]] in the trials, but it was not effective in improving [[muscle strength]], as measured by stair climb power.<ref name="pmid27535042" /><ref name="pmid32257854" /><ref name="pmid36479151" /><ref name="Businesswire2013" /> Consequent to these findings, enobosarm did not gain regulatory approval, and development for this use was terminated.<ref name="pmid32257854" /> Enobosarm had originally been under development for the treatment of sarcopenia (age-related muscle atrophy).<ref name="pmid32476495" /> However, the FDA requested a cardiovascular safety study be conducted to proceed with phase 3 trials for this indication.<ref name="pmid32476495" /> The developer of enobosarm refused to conduct this study due to the considerable costs that would be involved.<ref name="pmid32476495" /> 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.<ref name="pmid32476495" />

Following negative findings for muscle wasting, enobosarm was evaluated for the treatment of [[stress urinary incontinence]] in postmenopausal women.<ref name="AdisInsight" /><ref name="pmid32257854" /> It was expected that enobosarm might be effective for this use by strengthening the [[pelvic floor muscle]]s.<ref name="AdisInsight" /><ref name="pmid32257854" /> Enobosarm reached [[Phases of clinical research#Phase II|phase 2]] clinical trials for this indication, but development was discontinued due to lack of effectiveness in a phase 2 study.<ref name="AdisInsight" /><ref name="pmid32257854" />

Subsequently, enobosarm was repurposed again for the treatment of [[hormone-sensitive cancer|androgen receptor-positive (AR+) estrogen receptor-positive (ER+)]] breast cancer.<ref name="AdisInsight" /><ref name="pmid36972361" /> As of November 2023, it is in phase 3 clinical trials for the treatment of this type of breast cancer.<ref name="AdisInsight" /><ref name="pmid37946721" /><ref name="pmid37684290" /> Increases in lean body mass and muscle strength as a secondary benefit with enobosarm are also being evaluated in these women.<ref name="pmid32257854" /><ref name="KassemShohdy2019" /> These trials are notably employing several-fold higher doses of enobosarm than were assessed in the muscle wasting phase 3 trials (9{{nbsp}}mg/day versus 3{{nbsp}}mg/day, respectively).<ref name="pmid32257854" /><ref name="KassemShohdy2019" />

In January 2024, it was announced that enobosarm was being developed for prevention of muscle wasting and augmentation of fat loss in combination with [[GLP-1 receptor agonist|glucagon-like peptide-1 (GLP-1) receptor agonist]]s like [[semaglutide]] for [[weight loss]].<ref name="Biospace2024" /> A phase 2b clinical trial for this indication with 3 to 6{{nbsp}}mg/day enobosarm in sarcopenic obese or overweight elderly individuals is being prepared.<ref name="Biospace2024" />

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{{nbsp}}mg as of 2020.<ref name="pmid32476495" /><ref name="Biospace2016" /> However, enobosarm has not yet completed clinical development or been approved for any use.<ref name="AdisInsight" /><ref name="pmid32257854" />

== See also ==

* [[List of investigational sex-hormonal agents#Androgenics|List of investigational sex-hormonal agents § Androgenics]]

== Further reading ==

{{refbegin}}

* {{cite journal | vauthors = Crawford J, Prado CM, Johnston MA, Gralla RJ, Taylor RP, Hancock ML, Dalton JT | title = Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials) | journal = Current Oncology Reports | volume = 18 | issue = 6 | pages = 37 | date = June 2016 | pmid = 27138015 | pmc = 4853438 | doi = 10.1007/s11912-016-0522-0 }}

{{refend}}

== External links ==

* [https://adisinsight.springer.com/drugs/800022562 Enobosarm (GTx-024; MK-2866; Ostarine; S-22; VERU-024) - Veru Healthcare - AdisInsight]

{{Androgen receptor modulators}}

[[Category:Antiprogestogens]]

[[Category:Experimental cancer drugs]]

[[Category:Experimental drugs]]

[[Category:Hormonal antineoplastic drugs]]

[[Category:Nitriles]]

[[Category:Selective androgen receptor modulators]]

[[Category:Tertiary alcohols]]

[[Category:Trifluoromethyl compounds]]