Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate

the androgen receptor in specific tissues, promoting muscle and bone growth while having less
effect on male reproductive tissues like the prostate gland.
Non-selective steroidal drugs, called anabolic androgenic steroids (AAS), have been used for
various medical purposes, but their side effects limit their use. In 1998, researchers discovered a
new class of non-steroidal compounds, the SARMs. These compounds selectively stimulate the
androgen receptor, offering potent effects on bone and muscle to increase bone density and lean
body mass while having minimal impact on reproductive tissues.
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 2023, there are no SARMs which have been approved by the
United States Food and Drug Administration or the European Medicines Agency. 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[edit]
Steroidal androgens[edit]

Evolution of anabolic androgenic

steroids (top), non-steroidal antiandrogens and SARMs (middle), and SERMs (bottom)
[3] [4]
 Overlay of
the crystallographic structures of testosterone (cyan; PDB: 2AM9) with enobosarm
(green; PDB: 3RLJ) complexed with AR. Hydrogen bonds between AR residues Arg-752, Gln-
711, Asn-705 and the ligands are depicted as yellow dashes.
Anabolic androgenic steroids (AAS) are used to treat a variety of medical conditions, but their side
effects have fueled a search for a new class of drugs, with a better separation between desirable
anabolic and undesirable androgenic effects. The first clinically used AAS was testosterone which
was discovered in 1935 and first approved for medical use in 1939.[5] 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.[6][7] For most medical applications, an AAS with potent anabolic and minimal androgenic
and cardiovascular effects would be an advantage.
In the 1930s, 17α-alkylated anabolic steroids were discovered. These have increased metabolic
stability and are orally active, but are not tissue selective.[8] These alkylated anabolic steroids still
have significant androgenic effects, and are also hepatotoxic.[9][10] In 1950, nandrolone (19-
nortestosterone) was first synthesized, which is sometimes considered a SARM due to
greater tissue selectivity than testosterone.[8][10][11] In addition, 7α-alkyl substitution of testosterone (for
example trestolone) has also been reported to increase its anabolic effects.[8] However, efforts to
develop a steroid with anabolic but minimal androgenic effects were not successful.[12]
SERMs[edit]
Interest in nonsteroidal AR mixed agonist/antagonists increased after the therapeutic uses
of selective estrogen receptor modulators (SERMs) became evident.[13] The first SERM, tamoxifen,
was orginally developed as an anti-estrogen contraceptive. However it was discovered it promoted
ovalation in humans by acting as an agonist in ovaries. The drug was then
successfully repurposed as a treatment in breast cancer where it was found to act as a full
antagonist in breast tissue.[14] Somewhat unexpectedly, it was also discovered that tamoxifen
preserves bone density[15] by acting as an agonist in bone resorbing osteoclasts.[16] The clinical
success of SERMs stimulated interest in analogous tissue selective drugs that target the AR.[7]
Non-steroidal AR antagonists[edit]
The chemical starting point for AR mixed agonist/antagonists were nonsteroidal
AR antiandrogens such as flutamide, nilutamide, bicalutamide. These antagonists work by binding to
the AR to prevent androgenic action; this class of chemicals dates to the 1970s.[6][13] The discovery
of arylpropionamides, which share structural similarity with bicalutamide and hydroxyflutamide,
suggested a way to make compounds that bind to the AR and produce both anabolic and
antiandrogenic effects.[6] 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]
Non-steroidal SARMs[edit]
The first non-steroidal SARMs were developed 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 core structure. The name was adopted by
analogy with SERMs.[13] Other SARMs include tetrahydroquinolines, tricyclics, bridged
tricyclics, aniline, diaryl aniline, bicylclic hydantoins, benzimidazole, imidazolopyrazole, indole,
and pyrazoline derivatives.[6] 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.[7] Those that have advanced to human trials show stronger effects in bone and muscle
tissue and weaker effects in the prostate.[8]
Unlike most current forms of testosterone replacement, SARMs are orally bioavailable[7] and largely
eliminated via hepatic metabolism and metabolized through amide hydrolysis in the case of
arylpropionamides and A-ring nitro reduction of andarine.[9]
Proposed treatment of hypogonadism[edit]
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.[17][18][19] 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.[20][21] Estrogenic signaling in particular is essential for normal male
physiology and health, including for instance maintenance of bone strength.[22][23]

Mechanism[edit]
The mechanism of action of SARMs' tissue-specific effects continues to be debated as of 2020.[6][24] A
number of hypotheses have been advanced. These include the non-activation of SARMs by 5α-
reductase, tissue selective expression of androgen receptor coregulators, non-genomic signaling,
and tissue selective uptake of SARMs.[6][25]
5α-Reductase[edit]
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.[26] SARMs are not substrates of 5α-reductase, hence they are not selectively activated like
testosterone in tissues such as prostate.[10] This lack of activation effectively imparts a degree of
tissue selectivity to SARMs.[27]
Androgen receptor coregulators[edit]
Tissue selective transcription coregulator expression is another possible contributor to the selectivity
of SARMs.[28][25] Like other type I nuclear receptors, the unliganded androgen receptor (AR) resides in
the cytosol complexed with heat shock proteins (HSP). Upon ligand binding, the AR freed from
HSPs and translocated into the nucleus where it binds to androgen response elements on DNA to
regulate gene expression.[29] 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.[28][19] 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.[29] 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.[29]
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.[25][7] 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.[25]
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.[6][25]
Non-genomic signaling[edit]
In addition to the regulation of gene expression by nuclear AR, membrane associated AR is known
to have rapid non-genomic effects on cells through signal transduction cascades. Non-genomic
effects appear to significantly contribute to the anabolic effects of androgens whereas genomic
effects are primarily responsible for the development of male sexual organs. Furthermore, each
steroidal androgen or non-steroidal SARM uniquely influences distinct pathways depending on cell
type.[25]
Tissue distribution[edit]
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.[10]

Drug candidates