Selective androgen receptor modulator

Selective androgen receptor modulator
Drug class
Enobosarm (ostarine), a nonsteroidal SARM under investigation for potential medical use.
Class identifiers
Synonyms	Nonsteroidal androgen (although not all SARMs are nonsteroidal)[1]
Use	Investigational
Biological target	Androgen receptor
Chemical class	Mostly nonsteroidal

Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate the androgen receptor in certain tissues like muscle and bone over other tissues like the prostate gland and seminal vesicles.

Non-selective anabolic androgenic steroids (AAS) are potentially useful for a variety of medical conditions, but their use is limited by side effects. Attempts to find a steroid with anabolic effects in skeletal muscle and bone—increasing bone density and lean body mass—and negligible activity in other tissues were a failure. In 1998, researchers discovered a new class of nonsteroidal compounds (the SARMs) that selectively bind to the androgen receptor, granting them potent actions in muscle and bone with much less effect in reproductive tissues like the prostate gland and seminal vesicles.

SARMs have been investigated in human studies for the treatment of osteoporosis, cachexia (wasting syndrome), benign prostatic hyperplasia, stress urinary incontinence, and breast cancer. (As of 2020), there are no SARMs which have been approved by the United States Food and Drug Administration. Although adverse effects in clinical studies have been infrequent and mild, SARMs can cause elevated liver enzymes, reduction of HDL cholesterol levels, and hypothalamic–pituitary–gonadal axis (HPG axis) suppression, among other side effects.

Since the early twenty-first century, SARMs have been used in doping; they were banned by the World Anti-Doping Agency in 2008. SARMs are readily available on internet-based gray markets and are commonly used recreationally to stimulate muscle growth.

History

Evolution antiandrogens and SARMs (top)^[2] and SERMs (bottom)^[3]

Anabolic androgenic steroids (AAS), including those produced endogenously such as testosterone and dihydrotestosterone (DHT), bind to and activate the androgen receptor (AR) to produce their effects. AAS effects can be separated into androgenic (the development and maintenance of male sexual characteristics) and anabolic (increasing bone density, muscle mass and strength). AAS also affect hematopoiesis, coagulation, metabolism, and cognition.^[4][5] In the 1930s, 17α-alkylated anabolic steroids were discovered, which are sometimes considered SARMs due to greater tissue selectivity than testosterone.^[6][7][8] These steroids were formed by adding an alkyl group to the testosterone molecule, changing its binding affinity to the AR.^[9] 17α-Alkylated anabolic steroids still have significant androgenic effects, and are also hepatotoxic.^[7] Efforts to develop a steroid with anabolic but minimal androgenic effects were not successful.^[10]

Antiandrogens such as bicalutamide, flutamide, and nilutamide are nonsteroidal AR antagonists that work by binding to the AR to prevent androgenic action; this class of chemicals dates to the 1970s.^[4][11] Interest in nonsteroidal AR agonists increased after the therapeutic uses of selective estrogen receptor modulators (SERMs) became evident.^[11] The discovery of arylpropionamides, which share structural similarity with bicalutamide and hydroxyflutamide, suggested a way to make compounds that attach to the AR and produce both anabolic and antiandrogenic effects.^[4] Selective androgen receptor modulators (SARMs) were developed out of a desire to maintain the anabolic effects of androgens on muscle and bone, while avoiding side effects on other tissues such as the prostate and cardiovascular system.^[9]

Nonsteroidal SARMs were invented in 1998 independently by two research groups, one at the University of Tennessee that created an arylpropionamide SARM and Ligand Pharmaceuticals that made a SARM with a quinolone. The name was adopted by analogy with SERMs.^[11] Other SARMs include tetrahydroquinolines, tricyclics, bridged tricyclics, aniline, diaryl aniline, bicylclic hydantoins, benzimidazole, imidazolopyrazole, indole, and pyrazoline derivatives.^[4] SARMs can be agonists, antagonists, or partial agonists of the AR depending on the tissue, which can enable targeting specific medical conditions while minimizing side effects.^[5] Those that have advanced to human trials show stronger effects in bone and muscle tissue and weaker effects in the prostate.^[6] SARMs are orally bioavailable and largely eliminated via hepatic metabolism and metabolized through amide hydrolysis and A-ring nitro reduction.^[9]

Mechanism

The mechanism of action of SARMs' tissue-specific effects continues to be debated (As of 2020).^[4][12] A number of hypotheses have been advanced. These include the non-activation of SARMs by 5α-reductase, tissue selective expression of androgen receptor coregulators, tissue selective uptake of SARMs, and non-genomic signaling.^[4][13]

5α-Reductase

Testosterone is active in non-reproductive tissue without activation. In contrast, tissue selective activation by 5α-reductase to the more active form DHT is required for significant activity in reproductive tissue. The net result is that testosterone and its metabolite together are not tissue selective.^[14] SARMs are not substrates of 5α-reductase, hence they are not selectively activated like testosterone in tissues such as prostate.^[7] This lack of activation effectively imparts a degree of tissue selectivity to SARMS.

Androgen receptor coregulators

Tissue selective transcription coregulator expression is another possible contributor to the selectivity of SARMs.^[15][13] Like other type I nuclear receptors, the uncomplexed androgen receptor (AR) resides in the cytosol. Upon ligand binding, the AR is translocated into the nucleus where it binds to androgen response elements on DNA to regulate gene expression.^[16] AR agonists such as testosterone recruit coactivator proteins to AR that facilitate upregulation of gene expression while antagonists recruit corepressors which down regulate gene expression. Furthermore, the ratio of coactivators to corepressors is known to vary depending on tissue type.^[15][17] Structurally, pure AR agonists stabilize the position of helix-12 (H12) in the ligand binding domain of AR near H3 and H4 to produce a surface cleft that binds to a FxxLF motif contained in coactivators.^[16] Conversely, antagonists destabilize the agonist conformation of H12 blocking the binding of the FXXLF coactivator motif while facilitating the binding of the corepressor LXX(I/H)IXXX(I/L) motif found in NCOR1 and SMRT corepressors.^[16]

In analogy to SERMs, SARMs are mixed agonists/antagonists displaying agonist androgen receptor activity in bone and muscle and partial agonist or antagonist activity in other tissues such as prostate.^[13][5] Non-selective agonists such as testosterone are able to recruit coactivators when bound to AR but not corepressors and hence are agonists in all tissues. In contrast, SARMs can recruit both coactivators and corepressors by partially destabilizing the agonist conformation of H12. In tissues where coactivators are in excess (as in bone and muscle), SARMs act as agonists. Conversely, in tissues where corepressors are in excess (such as prostate), SARMs act as partial agonists or antagonists.^[13]

In vitro testing of the SARMs enobosarm (ostarine) and YK-11 showed that they bound to the AR, but unlike full AR agonists, they blocked interaction between the N-terminus and C-terminus of AR which resulted in a mixed agonist/antagonist mode of action.^[4][13]

Tissue distribution

Tissue selective uptake into anabolic tissues presents another potential mechanism for SARM tissue selectivity. However autoradiography studies with radiolabeled SARMs show no preferential distribution to anabolic tissues.^[7]

Drug candidates

SARM drug candidates^[18][11]

Name	Class	Developer	Investigated for	Highest development stage reached	Structure
Andarine (S-4, GTx-007)	Arylpropionamide	GTx, Oncternal Therapeutics[19]	Cachexia[19]	Phase I (discontinued)[19]
Arcarine (ORM-11984)[20]	Unknown[18]	Orion Corporation[20]	Benign prostatic hyperplasia, hypogonadism, osteoporosis[18]	Phase I (discontinued)[20][18]	Structure undisclosed[18]
Enobosarm (ostarine, GTx-024, MK-2866, S-22)	Arylpropionamide	GTx, Veru Healthcare[21]	Breast cancer, cachexia, muscular dystrophy, stress urinary incontinence[21]	Phase III[21]
DT-200 (GLPG-0492)	Imidazolidine-2,4-dione	ProSkelia, Akashi Therapeutics, Galapagos NV[22]	Muscular dystrophy, cachexia[22]	Phase I[18][22]
GSK-971086	Unknown[23]	GlaxoSmithKline[23]	Sarcopenia[23]	Phase I (discontinued)[23]	Structure undisclosed[23]
GSK-2849466	Unknown[24]	GlaxoSmithKline[24]	Cachexia, heart failure[24]	Phase I (discontinued)[24]	Structure undisclosed[24]
GSK-2881078	Indole	GlaxoSmithKline[25]	Cachexia[25][26]	Phase II[25]
LGD-2941 (LGD-122941)	Quinolinone	Ligand Pharmaceuticals[27]	Cachexia, sexual dysfunction, hypogonadism, menopause, osteoporosis[27]	Phase I (discontinued)[27]
LGD-4033 (VK5211, ligandrol)	Pyrrolidinebenzonitrile	Ligand Pharmaceuticals[28]	Muscle wasting due to hip fracture, cachexia, hypogonadism, osteoporosis[12][28]	Phase II[28]
LY305	N-arylhydroxyalkyl	Eli Lilly[29]	Osteoporosis[29]	Phase I[29]
MK-0773 (PF-05314882)	Steroid	GTx, Merck[30]	Sarcopenia, osteoporosis[18][30]	Phase II (discontinued)[18][30][31]
MK-3984	Benzylpropionamide	Merck	Sarcopenia[18]	Phase I[18]
OPK-88004 (LY-2452473, TT-701)	Indole	Eli Lilly, OPKO[32]	Benign prostatic hyperplasia, quality of life in prostate cancer, erectile dysfunction[32][33]	Phase II[32]
PF-06260414	Isoquinoline	Pfizer[34]	Cachexia[34]	Phase I (discontinued)[34]
PS-178990	Unknown[18]	Bristol-Myers Squibb, Ligand Pharmaceuticals[35]	Andropause, cachexia[35][18]	Phase I (discontinued)[35][36][18]	Structure undisclosed[18]
Vosilasarm (RAD140, EP0062, testolone)	Phenyloxadiazole	Ellipsis[37]	Breast cancer, osteoporosis, sarcopenia[38]	Phase I/II[38]
YK-11	Steroid	Toho University	Muscle wasting[39]	Preclinical

Certain anabolic steroids, like trestolone, dimethandrolone undecanoate, and 11β-methyl-19-nortestosterone dodecylcarbonate, have also sometimes been classed as SARMs.^[18]

Research and possible therapeutic applications

Due to their tissue selectivity, SARMs have the potential to treat a wide variety of conditions, including debilitating diseases. They have been investigated in human studies for the treatment of osteoporosis, cachexia, benign prostatic hyperplasia, stress urinary incontinence, prostate cancer, and breast cancer and have also been considered for the treatment of Alzheimer’s disease, Duchenne muscular dystrophy, hypogonadism and as a male contraceptive.^[17][5] (As of 2020), there are no SARMs which have been approved for therapeutic use by the United States Food and Drug Administration.^[17]

Most SARMs have been tested in vitro or on rodents, while limited clinical trials in humans have been carried out.^[4][40] Initial research focused on muscle wasting.^[13] Enobosarm (ostarine) is the most well-studied SARM; according to its manufacturer, GTx Incorporated, 25 studies have been carried out on more than 1,700 humans (As of 2020) involving doses from 1 to 18 mg each day.^[41][12] (As of 2020), there is little research distinguishing different SARMs from each other.^[4] Much of the research on SARMs has been conducted by corporations and has not been made publicly available.^[6]

Hypogonadism and hormone replacement therapy

Because of the potentially better side effect profile of SARMs compared to testosterone, SARMs have been proposed for use in the treatment of hypogonadism and for androgen replacement therapy.^[42][43][17] Phase I and II trials have provided preliminary evidence that the SARMs enobosarm and GSK-2881078 (in elderly men and postmenopausal women), and OPL-88004 (prostate cancer survivors with low levels of testosterone) increase lean body mass and muscle size with little effect on the prostate, supporting the potential of SARMs for use in hormone replacement therapy.^[9] However, it has been argued that SARMs are not ideal for use in androgen replacement therapy and could not replace testosterone in this context as they do not reproduce testosterone's full spectrum of effects, including androgenic potentiation via 5α-reduction and aromatization into estrogen.^[44][45] Estrogenic signaling in particular is essential for normal male physiology and health, including for instance maintenance of bone strength.^[46][47]

Benign prostatic hyperplasia

In rat models of benign prostatic hyperplasia (BPH), a condition where the prostate is enlarged in the absence of prostate cancer, SARMs reduced the weight of the prostate.^[40] OPK-88004 advanced to a phase II trial in humans, but it was terminated due to difficulty in measuring prostate size, the trial's primary endpoint.^[17]

Cancer

SARMs may help treat AR and estrogen receptor (ER) positive breast cancer, which comprise the majority of breast cancers.^[5][48] AAS were historically used successfully to treat AR positive breast cancer, but were phased out after the development of antiestrogen therapies, due to androgenic side effects and concerns about aromatization to estrogen (which does not occur with SARMs).^[48][13] Although a trial on AR positive triple negative breast cancer (which is ER-) was ended early due to lack of efficacy, enobosarm showed benefits in some patients with ER+, AR+ breast cancer in a phase II study. In patients with more than 40 percent AR positivity as determined by immunohistochemistry, the clinical benefit rate (CBR) was 80 percent and the objective response rate (ORR) was 48 percent—which was considered promising given that the patients had advanced disease and had been heavily pretreated.^[49][48] In 2022, the FDA granted fast track designation to enobosarm for AR+, ER+, HER2- metastatic breast cancer.^[50] Other SARMs such as vosilasarm have reached clinical trials in breast cancer patients.^[37]

Bone and muscle wasting

(As of 2020), there are no drugs approved to treat muscle wasting in people with chronic diseases, and there is therefore an unmet need for anabolic drugs with few side effects. One aspect hindering drug approval for treatments for cachexia and sarcopenia (two types of muscle wasting) is disagreement in what outcomes would demonstrate the efficacy of a drug. Several clinical trials have found that SARMs improve lean mass in humans, but it is not clear whether strength and physical function are also improved. After promising results in a phase II trial, a phase III trial of enobosarm was proven to increase lean body mass but did not show significant improvement in function. It and other drugs have been refused regulatory approval due to a lack of evidence that they increased physical performance; preventing decline in functionality was not considered an acceptable endpoint by the Food and Drug Administration. It is not known how SARMs interact with dietary protein intake and resistance training in people with muscle wasting.^[12][17]

Phase II trials of enobosarm for stress urinary incontinence—considered promising, given that the levator ani muscle in the pelvic floor has a high androgen receptor density—did not meet their endpoint and were abandoned.^[17][13]

Unlike other treatments for osteoporosis, which work by decreasing bone loss, SARMs have shown potential to promote growth in bone tissue. LY305 showed promising results in a phase I trial in humans.^[17]

Side effects

In contrast to AAS and testosterone replacement, which have many side effects that have curtailed their medical use, SARMs are well tolerated and have mild and infrequent adverse events in randomized controlled trials.^[40] SARMs are sometimes claimed to be non-virilizing (non-masculinizing).^[17][51] In actuality however, SARMs are largely uncharacterized clinically in terms of potential virilizing effects.^[4] In any case, as SARMs are not substrates for 5α-reductase and are not potentiated in 5α-reductase-expressing tissues like skin, hair follicles, and the prostate gland, they may be expected on a theoretical level to have reduced androgenic strength relative to testosterone in these tissues.^[52][53] SARMs cannot be aromatized to estrogen, thus causing no estrogenic side effects, for instance gynecomastia.^[54][17][5] Unlike most current forms of testosterone replacement, SARMs can be administered orally.^[5]

SARM use can cause elevated liver enzymes and reduction in HDL cholesterol.^[54][17] Transdermal administration via a skin patch may reduce these effects.^[17][29] Several case reports have associated SARMs with hepatocellular drug-induced liver injury when used recreationally,^[55] it is not known if the risk is significant for medical use.^[40][5] Whether SARMs increase the risk of cardiovascular events is unknown.^[40][5] SARMs have less effect on blood lipid profiles than testosterone replacement; it is not known whether androgen-induced HDL reductions increase cardiovascular risk; and SARMs increase insulin sensitivity and lower triglycerides.^[5][12]

Although they cause less suppression of the hypothalamic–pituitary–gonadal axis (HPG axis) than testosterone, studies have found that gonadotropins, free and total testosterone, and SHBG can be reduced in a compound- and dose-dependent fashion in men from SARM usage.^[4][12] Typically SHBG is reduced along with total testosterone and total cholesterol while hematocrit is increased. Most studies have found that follicle-stimulating hormone (FSH), luteinizing hormone (LH), prostate-specific antigen, estradiol, and DHT levels are not altered.^[40] Of SARMs that have been investigated, enobosarm is one of the least suppressive of gonadotropins, even in doses much higher than used in clinical trials. How the HPG axis is affected in women using SARMs is unknown.^[4][12] SARMs' effect in suppressing the gonadotropins FSH and LH is what makes SARMs potentially useful as a male contraceptive.^[56]

Non-medical use

Outside of pharmaceutical research, SARMs are a gray market substance produced by small laboratories and often marketed as a research chemical supposedly not for human consumption.^[4][57][58] Marketing SARMs for human consumption is illegal in some jurisdictions and has led to criminal convictions in the United States^[59] and the largest-ever fine levied under Australia's Therapeutic Goods Act 1989.^[60] Although SARMs are readily available for purchase on the internet, one study found that a majority of products advertised as SARMs online were mislabeled. Anecdotes and guides on usage can also be found online and on social media.^[61][54][5] Some compounds are commonly marketed for recreational use as SARMs despite having a different mechanism of action. These substances include ibutamoren (MK-677), which increases secretion of growth hormone; GW501516 (cardarine), an exercise mimetic that works as an agonist of the PPARβ/δ; and SR9009 (Stenabolic), an agonist of the Rev-Erb, which plays a role in circadian rhythm.^[4][62]

SARMs are used by bodybuilders and competitive athletes due to their anabolic and lack of androgenic effects,^[5] particularly in the United States, Europe, and other western countries.^[54] Some individuals using SARMs recreationally combine multiple SARMs or take a SARM along with other compounds, although there is no research on combining SARMs. The doses used often exceed those from clinical trials; nevertheless, the fat-free mass gained from SARMs is generally lower than what is obtained with moderate doses of testosterone derivatives.^[4] According to one study of SARM users, more than 90 percent were satisfied with their usage and 64 percent would take SARMs again even though a majority experienced adverse effects.^[63]

SARMs were banned by the World Anti-Doping Agency (WADA) in 2008.^[4] SARMs can be detected in urine and hair after consumption.^[64] WADA reported its first adverse analytical finding for SARMs in 2010 and the number of positive tests has increased since then; the most commonly detected SARMs are enobosarm (ostarine) and LGD-4033 (ligandrol).^[65][66] Athletes competing in the NFL, NBA, UFC, NCAA, and the Olympics have tested positive.^[55] There is limited evidence on how SARMs affect athletic performance.^[67]

Terminology

SARMs are sometimes also referred to as "nonsteroidal androgens",^[1][68] although not all SARMs are nonsteroidal in structure and steroidal SARMs also exist.^[18] The first SARMs, discovered in 1998, which were nonsteroidal, were initially referred to as nonsteroidal androgens.^[69] By 1999 however, on the basis of the selective estrogen receptor modulator (SERM)-like mixed agonist–antagonist and tissue-selective activity of these nonsteroidal androgen receptor agonists, the term "selective androgen receptor modulator" or "SARM" was introduced and started to be adopted.^[42] Despite its widespread use, the term "selective androgen receptor modulator" has been criticized by some authors, like David Handelsman, who argue that it is a misleading pharmaceutical marketing term rather than an accurate pharmacological description.^[44] He has also critiqued notions that SARMs isolate anabolic effects from so-called androgenic or virilizing effects, as has been previously claimed in the case of anabolic steroids.^{[44][70][71][72]}

References

{{Navbox

| name = Androgens and antiandrogens
| title = Androgens and antiandrogens
| state = collapsed
| listclass = hlist
| groupstyle = text-align:center;

| group1 = Androgens
(incl. AAS)

| list1 =

| group2 = Antiandrogens
| list2 = {{Navbox|child
| groupstyle = text-align:center;
| groupwidth = 9em;

  | group1 = AR antagonists
  | list1 =

  | group2 = Steroidogenesis
inhibitors

  | group3 = Antigonadotropins
  | list3 =

• D₂ receptor antagonists (prolactin releasers) (e.g., domperidone, metoclopramide, risperidone, haloperidol, chlorpromazine, sulpiride)
• Estrogens (e.g., bifluranol, [[diethylstilbestrol, estradiol, estradiol esters, ethinylestradiol, ethinylestradiol sulfonate, paroxypropione)
• GnRH agonists (e.g., leuprorelin)
• GnRH antagonists (e.g., cetrorelix)
• Progestogens (incl., chlormadinone acetate, [[cyproterone acetate, hydroxyprogesterone caproate, gestonorone caproate, [[Chemistry:Medroxyprogesterone medroxyprogesterone acetate, Chemistry:Megestrol acetate|megestrol acetate]])

  | group4 = Others
  | list4 =

• Androstenedione immunogens: Androvax (androstenedione albumin)
• Ovandrotone albumin (Fecundin)

}}

| liststyle = background:#DDDDFF;

| list3 =

• ^#WHO-EM
• ^‡Withdrawn from market
• Clinical trials:
  • ^†Phase III
  • ^§Never to phase III

See also

Androgen receptor modulators

Estrogens and antiestrogens

Progestogens and antiprogestogens

List of androgens/anabolic steroids

}}

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