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Selective androgen receptor modulators in
preclinical and clinical development
Ramesh Narayanan, Michael L. Mohler, Casey E. Bohl, Duane D. Miller and James T. Dalton
Corresponding Author: jdalton@gtxinc.com
Preclinical Research and Development, GTx, Inc., Memphis, Tennessee, USA (RN and MLM are co-first authors)
Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory
sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor
modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike
testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate
and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including
muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and
hypogonadism.This review summarizes the current standing of research and development of SARMs,
crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic
indications for this emerging class of drugs.
Received March 28th, 2008; Accepted November 12th, 2008; Published November 26th, 2008 | Abbreviations: ACS: American Chemical Society;
ADT: androgen deprivation therapy; AF-1: activation function-1; AF-2: activation function-2; AIS: androgen insensitivity syndrome; Akt: protein
kinase B; AR: androgen receptor; ARE: androgen responsive element; ASBMR: American Society for Bone and Mineral Research; BC:
bulbocavernosus; BFR: bone formation rate; BMC: bone mineral content; BMD: bone mineral density; BMS: Bristol-Myers Squibb & Co., Inc.; CaP:
cancer of the prostate; ChIP: chromatin immunoprecipitation; DBD: DNA binding domain; DHT: dihydrotestosterone; ER: estrogen receptor; FBM:
fat body mass; FSH: follicle stimulating hormone; GnRH: gonadotropin releasing hormone; GR: glucocorticoid receptor; GSK: GlaxoSmithKline;
HRT: hormone replacement therapy; HSP: heat shock protein; IC: intact control; IND: independent new drug application; J&J: Johnson & Johnson;
LA: levator ani; LBD: ligand binding domain; LBM: lean body mass; LH: luteinizing hormone; MAPK: mitogen-activated protein kinase; MR:
mineralocorticoid receptor; NCoR: nuclear receptor corepressor; NLS: nuclear localization sequence; NTD: N-terminal domain; ORX: orchidectomy;
PD: pharmacodynamics; PI3K: phosphatidylinositol-3-kinase; PK: pharmacokinetics; PR: progesterone receptor; PSA: prostate specific antigen;
SAR:structure activity relationship; SARM: selective androgen receptor modulator; SBMA: spinal bulbar muscular atrophy; SERM: selective estrogen
receptor modulator; SGRM: selective glucocorticoid receptor modulator; SMRT: silencing mediator of retinoid and thyroid receptors; SPRM: selective
progesterone receptor modulator; SRM: selective receptor modulator; SV: seminal vesicles; T: testosterone; Tfm: testicular feminization; THQ:
tetrahydroquinoline; TP: testosterone propionate; VP: ventral prostate | Copyright © 2008, Narayanan et al.This is an open-access article distributed
under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use, distribution and
reproduction in any medium, provided the original work is properly cited.
Cite this article: Nuclear Receptor Signaling (2008) 6, e010
Introduction
Androgens, the major circulating sex hormone in males,
regulate a broad spectrum of physiological processes
through an intracellular androgen receptor (AR)
[Bocklandt and Vilain, 2007; Leder, 2007]. Alteration in
the circulating level of androgens, modulation in AR
function through mutations or a change in the dynamic
intracellular AR complex leads to multiple disorders such
as hypogonadism, muscle wasting, cachexia,
osteoporosis, loss of reproductive function, prostate
cancer and others [Araujo et al., 2007; Brooke et al.,
2008; Leder, 2007; Morley et al., 2005].
The ubiquitous expression of AR and the steroidal
backbone of the natural ligands limit their use for
therapeutic purposes, factors which encourage the pursuit
of nonsteroidal tissue-selective androgen receptor
modulators (SARMs).The first SARMs were reported in
1998 [Dalton et al., 1998; Edwards et al., 1998]. Since
then, SARMs with a variety of structural scaffolds and a
range of tissue selectivity and specificity have been
discovered [Allan et al., 2007b; Manfredi et al., 2007].
The concept of tissue selective receptor modulators
(SRMs) evolved from selective estrogen receptor
modulators (SERMs), which have been clinically used for
over two decades to replenish the diminishing circulating
estrogens in postmenopausal conditions [Ward, 1973].
Efforts among the pharmaceutical and academic
communities to discover SRMs for other receptors such
as glucocorticoid receptor (SGRM) [Link et al., 2005;
Mohler, 2007a; Mohler, 2007b], progesterone receptor
(SPRM) [Tabata et al., 2003] and others are in progress.
Structure and function of androgen receptor
(AR)
AR belongs to the largest class of DNA binding
transcription factors, called nuclear receptors, comprised
of 48 members [Evans, 1988;Tsai and O'Malley, 1994].
Each member of this family has a crucial non-redundant
role and regulates critical biological functions in
vertebrates and non-vertebrates [Escriva et al., 1997; Lu
et al., 2006; Owen and Zelent, 2000]. Phylogenetic
studies indicate that the members are highly conserved
from the earliest metazoan [Owen and Zelent, 2000]. Of
the 48 receptors, 24-27 bind ligand with a characterized
ligand binding domain (LBD).The members of this family
are divided into three classes, with class I containing
receptors for estrogen, progesterone, mineralocorticoids,
glucocorticoids and androgens. Receptors for vitamin D,
retinoids and thyroids are categorized into class II. Class
III receptors are those for which ligands have not yet been
identified, and are hence classified as “orphans”.
However, in recent years, natural and synthetic ligands
for many of these orphan receptors have been uncovered
[Blumberg and Evans, 1998;Tsai and O'Malley, 1994].
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The AR DNA sequence is present in the X chromosome,
which has 8 exons spanning 90 kb sequences encoding
a 919 A.A. protein [Lu et al., 2006]. Like the PR and ER,
AR exists as 2 isoforms, AR and AR-A, formed by an
alternate translation start. Similar to PR-A, which lacks
the first 164 amino acids of PR-B, AR-A lacks the first
187 amino acids of AR. However, this isoform is not as
well characterized as PR or ER isoforms and its functions
remain unknown [Wilson and McPhaul, 1994;Wilson and
McPhaul, 1996]. AR, similar to the other members of the
class, contains four structural domains, with each
performing exclusive functions.The complete function of
the N-terminal domain (NTD) is still under investigation.
However, the activation function (AF-1) located in the
NTD plays a pivotal role in AR function. Unlike other
receptors, the NTD of AR is the major transactivation
domain and deletion of AF-1 leads to a significant loss of
AR function [Alen et al., 1999; Bevan et al., 1999; Gao
et al., 1996; Jenster et al., 1991; Simental et al., 1991].
In addition, the NTD is the major coactivator interaction
surface for AR and mediates the growth factor- and cell
signaling-dependent transactivation [Heinlein and Chang,
2002].The NTD of AR and other receptors have not yet
been crystallized. Structural knowledge of the NTD would
lead to better understanding of the function of this domain.
The DNA binding domain (DBD) is the most highly
conserved domain and, as the name indicates, is
responsible for the binding of AR to the promiscuous
androgen responsive element (ARE),
5'-AGAACANNNTGTTCT-3', on the promoter of androgen
responsive genes [Verrijdt et al., 2003].The DBD has 2
classical cysteine zinc finger motifs that are responsible
for DNA recognition and dimerization [MacLean et al.,
1997]. Each finger has 4 cysteines, 1 zinc atom, α-helices
and a carboxyl extension.This region has a highly
conserved 66-amino acid residue core referred to as P,
D, T and A boxes.The DBD crystal structure has been
solved both in the presence and absence of the DNA
elements [Shaffer et al., 2004].
The hinge region that lies between the DBD and the
ligand binding domain (LBD) is a lysine-rich region that
is important for the nuclear localization signal (NLS) of
the receptor [Gao et al., 1996;Ylikomi et al., 1992].
Deletion of this domain eliminates nuclear localization of
AR in the presence of ligand and, hence, loss of
transcriptional activity. Particularly, one amino acid
residue, Ser650, is critical for nuclear localization [Gioeli
et al., 2006]. Phosphorylation of Ser650 by p38 MAPK
prevents the nuclear localization of AR and subsequently
inhibits AR-mediated gene expression. Some prostate
cancer-specific mutations in the hinge suggest that the
hinge region plays a role in DNA binding and coactivator
recruitment [Tilley et al., 1996;Wang and Uchida, 1997].
The LBD of the receptor is responsible for ligand binding
and is not well conserved among the receptors. As
opposed to its family members, the LBD of AR is
comprised of only 11 helixes, due to the absence of helix
2 [Dehm and Tindall, 2007].The LBD forms a pocket to
capture the cognate ligand. In addition to the ligand
binding function, the LBD also contains a second
activation function (AF-2) that is important for the
ligand-dependent activation of the receptor. Further
details of the LBD and crystal structure are described
later.
Mechanism of AR action
In the absence of ligand, AR is maintained in an inactive
conformation by heat shock proteins HSP 70 and HSP
90 in the cytoplasm (Figure 1). Upon ligand binding, the
C-terminal helix 12 in the LBD shifts position to close the
ligand binding pocket. HSPs dissociate from the receptor,
leading to homo-dimerization.This facilitates a series of
conformational changes, with helices 3 and 5 serving as
the key interfaces following the dissociation of corepressor
complexes, leading to nuclear entry and binding to AREs
in the promoter of androgen-responsive genes.
Figure 1. Mechanism of action. AR is maintained in an inactive
complex by HSP 70 and HSP 90 and corepressors (CoR). Upon ligand
binding, the receptor homodimerizes and enters the nucleus.The receptor
is basally phosphorylated in the absence of hormone and hormone binding
increases the phosphorylation status of the receptor (P). The AR binds
to the ARE on the promoter of androgen responsive genes, leading to
the recruitment of coactivators (p160s, CBP, TRAP, ARAs) and general
transcription factors (GTF), leading to gene transcription.
Activated AR has been shown to recruit coregulators and
general transcription factors, subsequently leading to the
enhancement or repression of transcription of target
genes. Recent chromatin immunoprecipitation (ChIP)
studies indicated that ER and AR agonists recruit
coregulators cyclically in a time-dependent manner to the
respective response elements, indicating the complexity
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Review SARMs in development
and dynamicity of events occurring around these
response elements [Shang et al., 2000; Shang et al.,
2002;Wang et al., 2005]. After initiation of transcription,
AR leaves the DNA, and is targeted for ubiquitination,
proteolytic cleavage, and export out of the nucleus to the
cytoplasm. Another round of transcriptional activation
occurs with newly-synthesized receptor [Cardozo et al.,
2003; Fang et al., 1996; Pajonk et al., 2005].
To date, a number of clinical disorders of the AR have
been reported. Several mutations of AR LBD occur in
prostate cancer. A comprehensive list of mutations of AR
in prostate cancer can be found at the McGill Androgen
Receptor Gene Mutations Database World Wide Web
Server website [McGill_University, 2008]. Classical AR
functional abnormalities cause a spectrum of disorders
such as androgen insensitivity syndrome (AIS), testicular
feminization (Tfm), ablation of masculinization of
reproductive organs, osteoporosis and cachexia.
Another disorder that has been attributed to androgen
sensitivity due to an AR polymorphism is Kennedy’s
disease or spinal bulbar muscular atrophy (SBMA)
[Palazzolo et al., 2008]. AR has a stretch of polyglutamine
(CAG) repeats in the NTD varying in length between 12
and 25 amino acids, with an average between 21 and 22
[Palazzolo et al., 2008].The length of the CAG is inversely
proportional to AR activity. In Kennedy’s disease, the
number of CAG repeats range from 36 to 70, leading to
androgen insensitivity [Palazzolo et al., 2008]. In addition,
the inactive AR forms accumulate in the nucleus, leading
to cellular toxicity and neuro- and musculo-pathological
conditions [Palazzolo et al., 2007].
SARMs in clinical development
The field of nonsteroidal androgens, and especially
selective androgen receptor modulators (SARMs), has
grown tremendously since the first report in 1998. Many
of the major pharmaceutical companies have now
published in vivo characterizations of tissue selective AR
agonists, and the rate of new contributions to this field
continues to accelerate.The expansion of the field has
resulted in a broadening of the chemical space originally
occupied by the traditional steroidal agonists (not shown)
and nonsteroidal antagonists (compounds (1), (2), (3),
and (4); Figure 2), whose use is limited by prostate liability
and lack of tissue-selectivity, respectively.
Many chemically distinct putative AR agonist templates
have been reported, with fewer having demonstrated in
vivo tissue-selectivity for anabolic tissues (i.e., SARMs),
as summarized in Supplementary File 1. This
pharmacophoric diversity portends pharmacokinetic (PK)
and pharmacodynamic (PD) diversity across many
chemotypes, suggesting the potential for broad
therapeutic application for SARMs.The field of SARMs
will be reviewed with emphasis given to groups with the
most complete preclinical PK/PD characterizations, or
clinical data. Other excellent SARM reviews are available
[Allan and Sui, 2003; Buijsman et al., 2005; Cadilla and
Turnbull, 2006; Mohler et al., 2008; Mohler et al., 2005].
Clinical indications under investigation
Several groups have advanced SARMs to the clinic for
specific indications.The current clinical practices, followed
by the rationale and results (where available) of these
trials, are briefly discussed below.
Sarcopenia (GTx/Merck; Pharmacopeia/BMS; Ligand/TAP)
Age-related decline in lean body mass results in the
clinical condition known as sarcopenia in older individuals
[Marzetti and Leeuwenburgh, 2006]. An increase in the
elderly population has contributed to the growing number
of frail men and women that are unable to carry out
activities of daily living and are thus in need of
assisted-care.While enhancing protein intake and
exercise programs offer means to combat the muscle
loss that occurs with aging, hormonal therapy is likely to
show more drastic effects. An agent capable of selectively
increasing muscle performance without androgenic side
effects such as prostate growth in men and virilization in
women (side effects of steroidal androgens) is desirable
for the treatment of sarcopenia. A Phase IIa study with
the drug OstarineTM has shown significant improvement
in the ability of healthy, elderly men and women to climb
stairs, accompanied by significant increases in lean body
mass and decreases in fat mass after only 86 days
[Dalton, 2007a; Dalton, 2007b]. Lack of PSA increases
in men and hair growth in women further corroborated
selective anabolic effects of OstarineTM. Reductions in
serum lipids were observed. However, LDL/HDL ratios
remain in the low cardiovascular risk category.The
occurrence of adverse events were otherwise similar in
the placebo and treatment groups.Thus, clinical proof of
the benefits of SARM treatment for improving strength
exists and shows promise for treating age-related decline
in muscle strength, as well as other related indications
being pursued by Pharmacopeia (age-related functional
decline) and Ligand Pharmaceuticals (frailty), both having
completed Phase I trials.
Cancer cachexia (GTx/Merck)
Disease states that result in rapid loss of muscle are likely
to show significant benefit from SARM treatment.
Cachexia often occurs in patients with AIDS, cancer,
kidney disease, sepsis, and burns and is characterized
by weight loss, muscle wasting, and decrease in appetite.
Elevated levels of cytokines, namely IL-6, TNFα, INF 1β,
INFγ, and proteolysis inducing factor [Melstrom et al.,
2007] are thought to be the main contributors. At least
30% of cancer-related deaths result from cachexia due
to wasting of the respiratory muscles, which eventually
causes pneumonia [Palesty and Dudrick, 2003;Windsor
and Hill, 1988].While antibodies and inhibitors of
cytokines have shown benefit in chronic inflammatory
conditions such as rheumatoid arthritis and Crohn’s
disease, minimal efficacy has been shown in cachexia
treatment [Goldberg et al., 1995; Inui, 2002]. Appetite
stimulants including the synthetic progesterone derivative,
megestrol, and the synthetic cannabinoid, dronabinol,
are currently available in the United States, however side
effects of these drugs limit their benefit [Yeh et al., 2007;
Yeh and Schuster, 2006].Though megestrol causes
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Figure 2. Discovery of propionamide AR agonists in vitro and in vivo.The nonsteroidal antiandrogens (1-4) demonstrate therapeutic utility in
prostate cancer, and are structurally similar to some nonsteroidal tissue-selective agonists (i.e., SARMs). An early example of which was (5), which
was vastly improved by thioether to ether conversion, resulting in the prototypic SARM, S-4 (6). Preclinical characterizations of this molecule catalyzed
the development of the SARM field, as discussed herein and in the literature in general.
weight gain, its antianabolic properties result in decrease
in lean body mass despite weight gain [Lambert et al.,
2002]. Furthermore, the compound increases the risk of
thromboembolic events and suppresses adrenal function.
Likewise, problems with sedation and confusion in the
elderly limit the use of dronabinol [Volicer et al., 1997].
Studies with anabolic agents such as nandrolone for
cachexia have shown improvements in lean body mass
and bone density [Batterham and Garsia, 2001; Frisoli et
al., 2005], however side effects such as liver toxicity and
masculinization in women occur. Increases in lean mass
and muscle performance in HIV-infected men with wasting
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disorders upon testosterone treatment have also been
shown [Dolan et al., 2007; Grinspoon et al., 2000].The
proliferative effects on the prostate and elevation of
hematocrit remain drawbacks, however. An ideal SARM,
as first described by Negro-Vilar [Negro-Vilar, 1999], that
selectively increases muscle mass and lacks the growth
effect on prostate and increase in hematocrit, would make
androgen treatment a more beneficial option.
Improvement of muscle strength will conceivably result
in decreased morbidity and mortality in cachectic
individuals and may allow patients to undergo more
intensive treatments (e.g., radiation and chemotherapy
regimens). Currently, OstarineTM is in a Phase IIb clinical
trial for cachexia in cancer patients, with results expected
in 2008.
Osteoporosis (Ligand/TAP, GTx/Merck)
Preventing bone loss and increasing bone formation are
two mechanisms of protecting against osteoporosis. In
addition to calcium and vitamin D supplementation,
bisphosphonates are agents available to both men and
women.These drugs increase bone mineral density
(BMD) by inhibiting osteoclast activity [Fisher et al., 1999].
The role of estrogens in maintaining bone mass in women
is also crucial, as shown by the rapid decline in BMD in
postmenopausal symptoms. Hormone replacement
therapy (HRT) is commonly utilized to treat menopausal
symptoms, but is no longer recommended for long-term
treatment, due to increases in the risk of breast and
endometrial cancer, gallbladder disease, and
thromboembolism. SERMs such as tamoxifen and
raloxifene have thus replaced HRT treatment for
osteoporosis in women, as these agents selectively
maintain bone mass without proliferative effects in the
breast and uterus, but are associated with a higher risk
of venous thromboembolic events [Epstein, 2006; Ettinger
et al., 1999; Song et al., 2006]. Likewise, androgens are
known to have a positive effect on BMD through increase
in periosteal bone formation [Hanada et al., 2003].Their
importance in maintaining bone mass is further
exemplified by the occurrence of osteopenia in male AR
knockout mice [Kawano and Kawaguchi, 2006; Kawano
et al., 2003] and evidence that men undergoing androgen
deprivation therapy (ADT) for a prolonged period suffer
from decreases in BMD.The use of SARMs for
osteoporosis is likely to provide benefit in both men and
women, as they lack the side effects of virilization seen
with steroidal androgens. A 120-day study comparing
SARM S-4 and dihydrotestosterone (DHT) treatment in
ovariectomized rats demonstrated that S-4 was able to
maintain bone mass and bone strength to the levels of
intact controls and exhibited greater efficacy than DHT
[Kearbey et al., 2007]. Studies by Ligand Pharmaceuticals
with LGD2226 [Rosen and Negro-Vilar, 2002]
demonstrated increased bone mass and strength in rats
after 16 weeks of treatment.These effects are thought
to be mediated through AR in osteoblasts, thus increasing
the rate of bone formation.Therefore, combination
regimens with SARMs and currently available
bisphosphonates should provide a more efficacious
treatment option for osteoporosis. Currently, LGD2941
is in Phase I trials for osteoporosis (and frailty).
Possible future clinical indications
Prostate cancer
The first-line pharmacologic treatment option for patients
with androgen-dependent prostate cancer is ADT, which
includes a GnRH superagonist such as leuprolide to shut
down endogenous synthesis of testosterone with or
without an AR antagonist such as bicalutamide [Furr and
Tucker, 1996; Iversen et al., 2004;Wirth et al., 2004].
While the treatment is effective for slowing the cancer
growth, patients experience a number of side effects
including hot flashes, loss of libido, loss of lean body
mass, osteoporosis and a decrease in physical
performance [Clay et al., 2007; Malcolm et al., 2007;
Perlmutter and Lepor, 2007]. SARMs of varying agonist
activity have been discovered and shown to have a
wide-range of efficacy in animal models.While the more
potent agonists restore castrated rat prostate size back
to the intact control levels and muscle well beyond 100%
of the weight of the intact animals [Chen et al., 2005b;
Kim et al., 2005], other SARMs have been discovered
that restore muscle to nearly 100% with little increase in
prostate size compared with castrates [Gao et al., 2004].
Thus, a patient receiving leuprolide may benefit from
adjuvant SARM treatment to combat the side effects on
muscle and bone [Bahnson, 2007].
Male hormonal contraception
Despite prevalent use of oral contraceptives for women,
no oral pharmacologic option has been approved for men.
Hair et al. [Hair et al., 2001] found that desogestrel, an
oral synthetic progestin, in combination with a transdermal
testosterone patch, reversibly suppressed
spermatogenesis, but was not as efficacious as
combination testosterone injection regimens. Preclinical
studies in our laboratory have shown that propionamide
SARMs suppress luteinizing hormone (LH) and follicle
stimulating hormone (FSH) through the
hypothalamus-pituitary-testis axis in rats, thus decreasing
testosterone in a dose-dependent manner [Chen et al.,
2005a]. Furthermore, spermatogenesis was found to be
significantly decreased with 1 mg/day treatment for 10
weeks in these animals with the SARM, C-6 (see literature
for structure). Studies with the SARM, LGD2226,
assessing the effects on mating behavior of rats, show
maintenance of libido and sexual function in rats [Miner
et al., 2007]. As a whole, these data are encouraging
towards the development of a SARM as a male
contraceptive pill.
SARMs in preclinical development
GTx, Inc.– propionamide SARMs
Discovery of nonsteroidal SARMs (University of Tennessee
Health Science Center (UTHSC))
Dalton et al. unexpectedly discovered several nonsteroidal
ligands with the ability to fully stimulate in vitro
AR-dependent transcriptional activation.This
unprecedented activity was observed for propionamides
that differed slightly from hydroxyflutamide and
bicalutamide [Dalton et al., 1998; He et al., 2002b].
Compound (5), in which the sulfonyl-linkage and
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para-fluoro substituent of bicalutamide were replaced
with a thioether linkage and para-acetamide substituent,
respectively, emerged as an early lead from
structure-activity relationship (SAR) inquiries (Figure 2).
Compounds such as (5) demonstrated improved in vitro
agonist activity and avoided concerns related to the
chemical reactivity of the haloacetamides that were first
reported (Figure 2) [He et al., 2002b;Yin et al., 2003b].
Hydroxyflutamide analogs [Marhefka et al., 2001] and
non-propionamide templates were also explored with less
success [Yin et al., 2003b] (data not shown).
These thio-ether linked propionamides seemed very
promising, but suffered from a lack of the expected
pharmacologic activity in vivo, due to metabolic oxidation
of the thioether to sulfoxides or sulfones with little to no
agonistic activity [Yin et al., 2003c]. Elimination of
metabolic liability inherent in the sulfur group was
achieved with replacement of the thioether with an ether.
An in vivo pilot study in castrated rats demonstrated that
these AR ligands were capable of AR-dependent full
agonist activity in vivo, but also showed unprecedented
tissue-selective pharmacologic activity [Marhefka et al.,
2004;Yin et al., 2003a] in a typical Hershberger assay
(castration of male rats, followed by an androgen
treatment regimen and analysis of organs weight for
levator ani (LA) or other skeletal muscle as an indicator
of anabolic activity and seminal vesicles (SV) and/or
ventral prostate (VP) weight as indicators of androgenic
activity) [Hershberger et al., 1953]. Subsequently, the
Hershberger assay has become the assay of choice to
demonstrate tissue-selectivity in preclinical
characterizations of SARMs. Hershberger assays can be
performed in a maintenance mode (androgen treatment
immediately after castration) or restorative mode (waiting
period to allow atrophy prior to androgen treatment).The
ether-linked propionamides were selective, full anabolic
agonists with the ability to fully support the weight of
levator ani (LA) muscle, but weak partial agonists (or
antagonists) in androgenic tissues such as ventral
prostate (VP) and seminal vesicles (SV) (S-4 (6) in Figure
2). Molecules such as these were termed selective
androgen receptor modulators (SARMs) in analogy to
selective estrogen receptor modulators (SERMs), where
tissue-specific anabolic (bone maintenance) and
estrogenic (breast and/or uterine maintenance) activities
have been separated.
A potent SARM, S-4 (6), was identified that demonstrated
rapid and complete oral absorption at low doses and
reasonable elimination half-life (t1/2= 2.6 h to 5.3 h) in
rats, suggesting compounds such as this would be
excellent candidates for clinical development [Kearbey
et al., 2004]. S-4 (6) also demonstrated the ability to
improve skeletal (soleus) muscle strength, increase lean
body mass (LBM), reduce body fat, and prevent bone
loss in rats, in addition to promising pharmacologic activity
in animal models of benign prostatic hypertrophy and
male fertility [Chen et al., 2005a; Gao et al., 2004; Gao
et al., 2005; Kearbey et al., 2007].These successes
encouraged us to expand our efforts toward exploration
of the diaryl propionamide class of SARMs, many of which
have been published [Bohl et al., 2004; Chen et al.,
2005a; Chen et al., 2005b; Kim et al., 2005].
Clinical development (GTx, Inc.)
OstarineTM is an aryl propionamide SARM and the most
advanced clinical candidate. OstarineTM demonstrated
exciting data in an initial proof-of-concept Phase IIa
clinical trial. GTx, Inc. reported in December 2006 the
results of this clinical trial, which was a double blind,
randomized, placebo-controlled trial in sixty elderly men
and sixty postmenopausal women [Dalton, 2007a; Dalton,
2007b].Without a prescribed diet or exercise regimen,
all subjects treated with OstarineTM had a dose-dependent
increase in total LBM, with the 3 mg/day cohort achieving
an increase of 1.3 kg compared to baseline and 1.4 kg
compared to placebo after 3 months of treatment.
Treatment with OstarineTM also resulted in a
dose-dependent improvement in functional performance
measured by a stair climb test, with the 3 mg/day cohort
achieving clinically significant improvement in speed and
power. Interestingly, subjects treated with 3 mg/d of
OstarineTM had on average an 11% decline in fasting
blood glucose, a 17% reduction in insulin levels, and a
27% reduction in insulin resistance (homeostasis model
assessment) as compared to baseline, suggesting that
SARMs might have therapeutic potential in diabetics or
people at risk for diabetes. Phase I clinical studies with
OstarineTM showed that it was rapidly absorbed after oral
administration with a half-life of about 1 day (unpublished
data). An additional Phase II study in muscle wasting
associated with cancer cachexia began in 2008 as an
early objective of clinical development. OstarineTM also
resulted in a dose-dependent decrease in LDL and HDL
cholesterol levels, with the average LDL/HDL ratio for all
doses remaining in the low cardiovascular risk catergory.
GTx, Inc. and Merck & Co., Inc. announced an agreement
providing for research and development, and global
strategic collaboration for their respective SARMs
programs.
Ligand Pharmaceuticals, Inc.– quinolinones
(pyridones) and derivatives
Ligand was an early leader in the development of
nonsteroidal AR ligands with their series of tricyclic
quinolinones [Edwards et al., 1999; Edwards et al., 1998;
Hamann et al., 1999; Higuchi et al., 1999]. Ligand has
published and patented an extensive array of bi-, tri-, and
tetracyclic (not shown) quinolinone templates, with bi-
and tricyclics demonstrating high affinity and potent
tissue-selective anabolic agonist activities.The structural
core of this series is a quinolinone (also known as
pyridone) A-ring, which occupies a space in the receptor
similar to the steroidal A-ring (discussed infra).The
earliest members of this class were antagonists such as
LG-120907 (7), which bound with a Ki value of 26 nM
(Figure 3) (US Patent 6,017,924 [Edwards et al., 2000])
and inhibited testosterone-induced increases in VP and
SV tissue weights (ED50 [VP] = 18.3 mg/kg; ED50 [SV] =
19.2 mg/kg). Changing the A-ring from the
α,β-unsaturated quinolinone to a coumarin (representative
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Review SARMs in development
example (8)) within a 2,2-dimethyl substituted pyridone
template retained antagonist activity; however, changing
the alkylation pattern from 2,2-dimethyl to 4-ethyl such
as in LGD121071 (9) produced an early high affinity,
potent AR full agonist in in vitro transcriptional studies (Ki
= 17 nM; in vitro EC50 = 4 nM; 100%) [Hamann et al.,
1999].This α,β-unsaturated quinolinone became a
conserved feature in subsequent Ligand agonist series.
Higuchi et al. has explored two distinct oxazino variant
templates exemplified by (10-11) and (12), respectively
[Higuchi et al., 2007b]. In their initial efforts, they
characterized their 7H-[1,4]oxazino(3,2-g)quinolin-7-ones
(an anthracene-like fused ring system) and showed
tissue-selective myoanabolic activity (see compound (10)
in Figure 3) (US Patent 6,462,038 [Higuchi et al., 2002]).
Recently, this group published an in vitro SAR of this
template series and an in vivo characterization of (11),
(as outlined in Figure 3) which differs from (10) by the
addition of an (R)-methyl group α to the oxazino nitrogen.
This work demonstrated some tolerance in vitro to various
substitutions at the N, and carbons α and β to the nitrogen
of this oxazino ring system [Higuchi et al., 2007a].
Separately, Higuchi et al. characterized a template of
constitutional isomers, the
8H-(1,4)oxazino(2,3-f)quinolin-8-ones, which were
incidentally formed as a minor product in the synthesis
of (11) [Higuchi et al., 2007a]. Serendipitously, these new
phenanthracene-like oxazino isomers also demonstrated
AR agonist activity. Similar to the anthracene
configuration oxazines (i.e., (10-11)), these new oxazino
isomers were antagonists if the oxazino nitrogen
substituent was removed. Likewise, these
phenanthrenoids were sensitive to the substituent present
at the oxazino nitrogen (R1= allyl and CH2CF3 are
optimal) and the carbon α to it (R2= Et and iPr are
optimal).In vitro characterization identified (12) (i.e., R1=
CH2CF3, R2= (R)-Et) as a lead for in vivo proof-of-concept
studies for this template in which (12) demonstrated
selective myoanabolism in a maintenance Hershberger
assay (i.e., treatment immediately after castration), as
shown in Figure 3.
Clinical candidates thus far from this group have been
bicyclic 6-anilino quinolinones in which the aniline was
generally disubstituted such as in (13), that demonstrated
tissue-selective full myoanabolic activity [van Oeveren et
al., 2007a]. Ligand chose LGD2226 (14) as its first
pre-clinical lead compound. Although development of
LGD2226 (14) was later discontinued, Ligand scientists
published characterizations of LGD2226 (14) with regard
to the SAR for similar compounds [van Oeveren et al.,
2007a; van Oeveren et al., 2007b], discovery/organic
synthesis [van Oeveren et al., 2006], co-crystal structure
with AR [Wang et al., 2006] (discussed infra), myo- and
osteoanabolic activity, and maintenance of sexual function
in castrated rats [Miner et al., 2007]. LGD2226 (14)
demonstrated myoanabolism weaker than testosterone
and osteoanabolism which was shown to increase bone
mineral density (BMD), improve bone structure and
strength, and positively affect bone biomarkers.
In 2005, Ligand filed an investigational new drug
application (IND) for LGD2941 (15), which is currently in
Phase I clinical trials for frailty and osteoporosis in
collaboration with TAP Pharmaceuticals (an Abbott
subsidiary). A recent publication characterized the
pre-clinical osteo- and myoanabolic properties of
LGD2941 in rats (15) [Martinborough et al., 2007; Wang
et al., 2006]. LGD2941 (15) demonstrated improved
bioavailability relative to LGD2226 (14), while maintaining
hypermyoanabolic and hyperosteoanabolic properties in
male and female in vivo maintenance models.The
myoanabolism was seen as 180% and 100% of LA weight
retention at 10 and 1 mg/kg, respectively, compared with
100% and 50% of VP weight retention at the same doses.
The osteoanabolism was seen as a small increase in
lumbar space compression strength (46 N vs. 43 N for
intact control) and larger increases in femur bending
strength (230 N vs. 175 N for intact control), indicating
effectiveness in cancellous and cortical bone,
respectively. In each case, these bone effects were in
excess of those seen for estradiol and DHT.
A third compound in preparation for clinical testing,
LGD-3303 (structure not disclosed), was recently reported
at the 2007 American Society for Bone and Mineral
Research (ASBMR) Meeting (unpublished data).
LGD-3303 is a hypermyoanabolic and osteoanabolic
agonist in rats with an LA Emax of 220%, but also
supports 100% of prostate at this dose.The dose for
100% LA support is 1 mg/kg per day and prostate support
at this dose is only ~20%. Ligand performed a pre-clinical
bone characterization in a postmenopausal rat model
(ovaries removed, followed by 8 week waiting period,
before a 12 week treatment period) that demonstrated
improvements in BMD (0.19 g/cm2 for LGD-3303 vs. 0.175
g/cm2 for control), femur mechanical strength (230 N for
LGD-3303 vs. 190 N for control), and trabecular bone
volume (14% for LGD-3303 vs. 10% for control) compared
to untreated ovariectomized control. LGD-3303 alone did
not fully recover BMD or trabecular volume as compared
with sham operated intact females.
Kaken Pharmaceutical Co., Ltd –
tetrahydroquinolines (THQ)
Kaken built their compounds around the bicyclic THQ
and tricyclic 3,4-cyclopentano THQ scaffolds (Figure 4)
and disclosed structure-activity relationships for the
binding to AR based on THQ substitution patterns (US
Patent 6,777,427 [Miyakawa et al., 2004a]). Substitution
at the 2- and 4-positions of the THQ ring with a variety of
groups led to the identification of a series of analogs with
7-fold higher affinity than hydroxyflutamide. S-40503 (16)
was selected for their initial in vivo studies. S-40503 (16),
when administered for 4 weeks to castrated rats beginning
immediately after surgery exerted androgenic effects,
and partially restored the prostate back to a normal level
(78 mg/100 g of body weight for S-40503 (16) treated,
castrated rats versus 9 mg/100 g of body weight for
untreated castrated rats).This compound was also
reported to maintain BMD in males at a comparable level
with control animals (Figure 4). A similar study was
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Review SARMs in development
Figure 3. Quinolinone (pyridone) fused-ring SARMs. Ligand Pharmaceuticals, Inc. thoroughly explored the structural space surrounding their
core quinolinone motif (ring A). SARM activity was achieved using several related templates including: tetrahydropyrido[3,2-g]-quinolin-2(1H)-one (9);
anthracenoid (7H-[1,4]oxazino(3,2-g)quinolin-7-ones) (10-11) and phenanthroid (8H-(1,4)oxazino(2,3-f)quinoline-8-ones) (12) oxazino variants; and c)
6-anilino quinolinones (13-15).This latter class produced two clinical candidates in collaboration with TAP Pharmaceuticals. Data shown for (7) and
(10) are derived from US Patents US 6,017,924 and 6,462,038, respectively. IC is an abbreviation for intact control. Other abbreviations are as described
in the text.
performed in ovariectomized (i.e., removal of the ovaries,
which are the primary estrogen producing gland in
females) female rats, but a waiting period of four weeks
was added before they were treated with S-40503 (16)
for 8 weeks (i.e., a restorative or postmenopausal model).
DHT was used as a positive control. S-40503 (16) also
increased BMD in female ovariectomized rats, indicative
of osteoanabolic activity, and had the same or better
anabolic effects as DHT (Figure 4). Hanada et al. [Hanada
et al., 2003] further characterized the osteoanabolic
activity of S-40503 (16) by showing it increased BMD and
biomechanical strength of femoral cortical bone compared
to estrogen, an antiresorptive agent that does not increase
these parameters (not shown).They also demonstrated
the expected myoanabolic activity in LA at 30 mg/kg to
be greater than intact control, but less than DHT at 10
mg/kg. Unfortunately, when S-40503 (16) was
administered for an 8-week period to castrated rats, the
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Review SARMs in development
prostate weight was restored to the level of the control,
illustrating it also showed full androgenic agonist activity.
To our knowledge, S-40503 (16) was not advanced to
clinical trials.
Kaken also explored a variety of tricyclic THQ derivatives
similar to some of Ligand’s tricyclic quinolinone templates.
However, the templates from Kaken have the nitrogen in
the B-ring, which is always saturated (i.e.,
tetrahydroquinoline (THQ); Figure 4). Early patents
demonstrated in vivo osteo- and myoanabolic activities
for molecules with 3 distinct C-rings: 1.) cyclopentene
(World patent application WO2001 027086 [Hanada et
al., 2001]), 2.) cyclopentane (World patent application
WO2004 013104 [Miyakawa et al., 2004b]), and 3.)
tetrahydrofuran (World patent application WO2004
000816 [Miyakawa et al., 2004c]).
An exemplary compound (17) of the cyclopentene
template (template 1 in Figure 4), when administered at
5 days post-castration at 60 mg/kg for 4 weeks increased
VP weights (56 mg/100 g body wt.) relative to
vehicle-treated, castrated (9 mg/100 g body wt.), but did
not approach the positive control of 10 mg/kg DHT (150
mg/100 g) or sham (i.e., intact) control (104 mg/100 g),
demonstrating partial agonist activity in VP. Although
BMD for (17) was comparable to DHT and sham controls,
the difference between vehicle-treated castrated and
sham was small (124 mg/cm2 vs. 132 mg/cm2).
Compounds (18) and (19) were shown to partially prevent
testosterone-induced increases in prostate size in
castrated rats treated with testosterone, suggesting that
these compounds may be useful in the treatment of
prostate cancer (CaP), prostatic pre-malignancies such
as prostatic intraepithelial neoplasia (PIN) and proliferative
inflammatory atrophy (PIA) [De Marzo et al., 2007], and
benign prostatic hyperplasia (BPH), or other androgenic
prostatic maladies.
Compound (20) (template 2 in Figure 4) is an example
of the Kaken template with the cyclopentane ring fused
to the 3,4 positions of the THQ ring system. Compound
(20) (30 mg/kg) partially increased VP weight as
compared to intact controls (70 mg/100 g vs. 94 mg/100
g), but demonstrated full osteoanabolic activity and
hypermyoanabolic activity. Compounds (21), (22), and
(23) demonstrated full myoanabolic activity, with
androgenic effects in the prostate varying from partial to
full, demonstrative of the unique characteristics of these
and other SARM pharmacophores on a
molecule-by-molecule basis.The tetrahydrofuran variants
with oxygen at the 4-THQ position of the THQ nucleus
such as in (24) (template 3 in Figure 4) also demonstrated
full myo- and osteoanabolic SARM activity (World patent
application WO2004 000816 [Miyakawa et al., 2004c]).
Despite multiple early and thorough demonstrations of
tissue-selective hypermyoanabolic and osteoanabolic
activities from several related structural templates, no
clinical candidates are known from Kaken.
Bristol-Myers Squibb & Co., Inc. (BMS) SARMs
– hydantoins and variants thereof
BMS has a very broad portfolio of AR ligands, many of
which are antagonists [Balog et al., 2004; Salvati et al.,
2005a; Salvati et al., 2005b]. Examples of the diversity
within the patented AR ligand template portfolio have
been recently reviewed [Mohler et al., 2008].The A-rings
are typically naphthyl or trisubstituted phenyl aniline
derivatives (representative examples in Figure 5). BMS
reported mutagenicity associated with the naphthyl aniline
hydrolytic metabolites and the ability to design out these
problems using trisubstituted phenyl A-rings which are
para cyano/nitro, meta halogen and ortho methyl anilines
[Hamann et al., 2007]. Separately, BMS explained how
to convert certain of their antagonists into agonists with
SARM activity [Sun et al., 2006]. Figure 5 illustrates how
BMS obtained potent and selective SARM activity by
simplifying the B-ring to a [5.5] bicyclic hydantoin, which
has a hydroxyl substituent properly located to interact
with N705 (contrast (25b) and (26)).
In addition to optimizing the aryl aniline (i.e., A-ring)
portion of their SARMs, BMS has also explored variants
of the [5.5] hydantoin ring system (i.e., B-ring), as
illustrated in Figure 5 (middle).The optimal molecule in
each case has the same p-CN, m-Cl, and o-methyl
substituted aniline A-ring (i.e., optimized to be
non-mutagenic), which provides the desired 58-62° aryl
ring to hydrantoin ring dihedral angle [Manfredi et al.,
2007].The first hydantoin variant replaces the 3-oxo
group of (26) with a sulfonyl group, a change which was
postulated to reduce aniline release in vivo [Manfredi et
al., 2007]. Also explored within the sulfone template, was
the reduction of the other hydantoin C=O (not shown).In
vitro results suggest the reduced template retains tight
binding, but has poor transactivational ability. Moreover,
the stereochemistry of the hydroxyl group is very
important for binding affinity and in vitro activity.The most
potent and selective compound, (27) in Figure 5, was
characterized as a tissue-selective partial myoanabolic
agonist in a restorative in vivo assay (i.e., waiting period
to allow diminution of tissues between castration and
treatment).
A second hydantoin variant (represented by (28) in Figure
5) involves the replacement of one of the C=O groups of
the hydantoin moiety with small alkyl groups, forming an
imidazolin-2-one-containing [5.5] ring system.This design
concept emerged from crystallographic studies which
demonstrated that this C=O makes no direct contacts
with the AR, and may be replaced with a hydrophobic
group [Li et al., 2007]. Also explored in this work were α,
β-unsaturated and saturated cyclic amide variations on
the hydantoin theme (not shown) which retained
significant affinity and in vitro activity, but demonstrated
poor in vivo activity. Compound (28) was the only
molecule that demonstrated full myoanabolic efficacy in
the same restorative assay as for (27). Cumulatively,
these results (and similar templates from Johnson &
Johnson, as discussed infra) suggest that the AR is
tolerant to a wide variety of rigidified [5.5] bicyclo ring
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Review SARMs in development
Figure 4. Tetrahydroquinoline (THQ) SARMs. S-40305 (16) was extensively characterized for its osteoanabolic activity by Hanada et al. Additionally,
Kaken scientists patented SARM activity for tetrahydroisoquinoline (THQ) templates 1, 2, and 3. Note that some or all of the data presented for (16-24)
was derived from the indicated patents. RBA is an abbreviation for relative binding affinity. Other abbreviations are as described in the text.
systems with variable sensitivity to the stereochemistry
of the hydroxyl carbon across the different templates.
BMS has published the preclinical characterization of
their only clinical candidate, BMS-564929 (29), which
combines the low mutagenicity A-ring already discussed
with a [5.5] hydantoin B-ring, as exemplified by (26)
[Ostrowski et al., 2007;Wilson, 2007]. BMS-564929 (29)
is a potent and hyperanabolic agonist compared to
testosterone in skeletal muscle (LA) with an efficacy of
125% (comparable to other SARMs) and high potency
(ED50 = 0.0009 mg/kg), with hypostimulation of the
prostate relative to testosterone (ED50 = 0.14 mg/kg). As
illustrated in Figure 5, these experiments in castrated rats
demonstrated a 160-fold selectivity for LA compared to
prostate, which they characterized as ‘unprecedented
muscle vs. prostate selectivity.’ However, BMS may have
over-estimated the selectivity of their compound, as
evidenced by irregularities in the dose response curves
and size of the prostate and LA muscle in castrated rats.
Further, the limiting factor for this compound is the 9-fold
selectivity between muscle action (i.e., myoanabolic
activity) and LH suppression (ED50 = 0.008 mg/kg). LH
suppression may cause side effects, especially in elderly
men, due to suppression of endogenous testosterone
and subsequently estrogen levels, leading to detrimental
effects on multiple organs systems including
pro-osteoporotic changes in bone. BMS-564929 (29) is
reported to be in Phase I clinical trials for age-related
functional decline. In October 2007, BMS licensed their
SARM program including BMS-564929 (29) (now
PS178990) and various back-up compounds to
Pharmacopeia Drug Discovery.
Johnson & Johnson (J&J)
Benzimidazole, imidazolopyrazole, indole, hydantoin and
pyrazole SARMs
J&J and its subsidiaries initiated comprehensive SARM
and AR antagonist programs and demonstrated
tremendous pharmacophore diversity, several for which
tissue-selectivity has been demonstrated. In addition to
multiple patent series, J&J has published in vivo SARM
characterizations belonging to five chemically distinct
templates (Figure 6): 1.) benzimidazoles [Ng et al., 2007a;
Ng et al., 2007b; Ng et al., 2007c]; 2.) imidazolopyrazoles
[Zhang et al., 2007b]; 3.) indoles [Allan et al., 2007a;
Lanter et al., 2006; Lanter et al., 2007]; 4.) hydantoin
variants [Zhang et al., 2006a]; and 5.) pyrazoles [Zhang
et al., 2007a].
Some of the published benzimidazole compounds were
characterized as potent and efficacious myoanabolic
SARMs. For instance, (30) is a
2-(2,2,2)-trifluoroethyl-benzimidazole which when dosed
at 2 mg/kg supported 126% LA weight (compared to 1
mg/kg testosterone) with an ED50 of 0.03 mg/d, but with
little stimulation of the prostate [Ng et al., 2007a],
demonstrating an activity profile comparable to other
hyperanabolic SARMs. Other molecules in the
benzimidazole class were recently characterized as AR
antagonists [Ng et al., 2007a; Ng et al., 2007b].
Compound (32) of template 2 (Figure 6), the
imidazolopyrazoles, was characterized as a potent (ED50
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Review SARMs in development
Figure 5. Conversion of antagonist to agonist, elimination of mutagenic potential, and various hydantoin replacements. Bristol-Myers
Squibb (BMS) extensively explored antagonist templates and demonstrated the conversion of antagonist templates into agonist templates using a
fragmentation approach.This group also explored several [5.5] bicyclic templates as alternatives to their [5.5] bicyclic hydantoin template of BMS-564929
(29). BMS-564929 (29) was characterized as a high potency myoanabolic SARM with high in vivo selectivity as related to the prostate, but a relatively
narrow therapeutic index with regard to LH suppression. BMS licensed their SARM program to Pharmacopeia Drug Discovery, including BMS-564929
(29) (now PS178990).
= 0.07 mg/d) but a relatively less efficacious (91% at 3
mg/kg) myoanabolic SARM, and also demonstrated less
tissue-selectivity than (30). Several articles characterizing
compounds of template 3 (Figure 6), the indoles, were
recently published, with only JNJ26146900 (33)
demonstrating tissue-selective activity [Allan et al.,
2007a]. JNJ26146900 (33) retains LA weight but reduces
prostate weight in intact animals, and partially offsets
castration-induced losses in BMD and LBM. JNJ26146900
(33) blocked testosterone-induced prostate cancer growth
and demonstrated favorable activity in a prostate cancer
xenograft model using CWR22-LD1 prostate cancer cells
(Figure 6).Template 4, the hydantoin derivatives, are
structurally similar to BMS-564929 (29) and other [5.5]
templates reviewed supra, and J&J template 2, the
imidazolopyrazoles. Based on (34) (ED50 = 2.9 mg/d),
they have SARM activity with lower myoanabolic potency
than (30) and (32) above, and variable myoanabolic
efficacy for (34) (75%) and (35) (117%) (Figure 6).
Template 5, the pyrazoles, were recently published, with
the lead molecule (36) shown in Figure 6 demonstrating
relatively weak potency (ED50[LA] = 3.8 mg/kg; Emax =
120%) myoanabolism. Compound (36) demonstrated
mixed agonist/antagonist effects in the prostate (28% at
2 mg/d for 5 days in castrated rats and 33% prostate
weight inhibition at 30 mg/d in intact rats), suggesting
possible utility in prostatic maladies.
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Review SARMs in development
Figure 6. Peer-reviewed SARMs from Johnson & Johnson (J&J) and subsidiaries. J&J published a wide variety of AR ligand templates, many
of which have demonstrated SARM activity (Templates 1-5). These compounds covered a broad range of pharmacological profiles and chemotype
diversity. Additionally, J&J patented a wide variety of propionamide bioisosteres (37-41), some of which have not been published. ORX, T, TP, and
CaP are abbrevations for orchidectomy, testosterone, testosterone propionate, and prostate cancer, respectively. Other abbreviations are as described
in the text.
Johnson & Johnson Co. and subsidiaries – cyclic
bioisosteres of propionamides
Johnson & Johnson scientists patented a wide variety of
diaryl templates in which the propionamide linker segment
has been replaced by a variety of cyclic elements to
include: thiazolines (37) (World patent application
WO2004 113309 [Ng and Sui, 2004]), pyrazoles (38) (US
patent application US2006 0211756 [Zhang et al.,
2006b]), imidazolin-2-ones (39) (US patent application
US2006 0063819 [Lanter and Sui, 2006]), diaryl indoles
(40) (US patent application US2005 245485 [Lanter et
al., 2005b]), and pyrrolopyridines (41) (US patent
application US2005 250741 [Lanter et al., 2005a]).
Representative examples of each bioisosteric template
are shown in Figure 6 (bottom right).
Although the pharmacophoric diversity embodied in the
AR ligand portfolio advanced by J&J and subsidiaries is
impressive, the patents only disclose tissue-selectivity in
qualitative terms, with no quantitative measures of
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Review SARMs in development
pharmacologic activity or structure-activity relationship.
The published literature does outline a number of
significant advances in tissue-selective modulation, as
discussed supra. Nonetheless, J&J does not appear to
be pursuing clinical development of a SARM at this time.
Merck & Co., Inc.
Azasteroidal SARMs
Merck scientists patented a variety of steroidal SARMs
which were variations of the 4-azasteroidal template of
finasteride, a 5α-reductase inhibitor. Modifications at
several positions reportedly produce tissue-selective
activity, with agonist activity in bone and muscle and
antagonist activity in prostate or uterus. Some of the
points of variation included fluorination of the A-ring
(World patent application WO2003 077919 [Meissner and
Perkins, 2003]), substitution at the 4-[all azasteroidal
patents discussed herein], 6- (US patent application
US2004 0235808 [Wang, 2004]), and 7- (World patent
application WO2004 0100874 [Meissner and Perkins,
2004]) positions, and addition of an imidazole ring fused
to the 3 and 4 positions (World patent application
WO2006 0026196 [Wang and Close, 2006]).The most
conspicuous changes occur at the 17β position.These
17β substituents are a wide variety of nitrogen-linked aryl
groups which includes carboxamides and acetamides
(World patent application WO2005 0005606 [Dankulich
et al., 2005a];World patent application WO2005 009949
[Dankulich et al., 2005];World patent application WO2005
099707 [Wang and McVean, 2005]; US patent application
US2006 0258661 [Dankulich et al., 2006]), amines (US
patent application US2006 0241107 [Meissner and
Perkins, 2006]), C17 heterocyclics (World patent
application WO2005 0025579 [Meissner and Mitchell,
2005]), and C20 heterocyclics (World patent application
WO2005 004807 [Dankulich et al., 2005b]) (see Figure
7, top left for atom numbering). Merck reported data at
the 2007 National American Chemical Society (ACS)
Meeting to substantiate their claims of SARM activity with
an azasteroidal template. A series of
17-hydroxy-4-azasteroids was analyzed in an in vitro
transactivation assay. This SAR information was used to
select the azasteroid (42) shown in Figure 7 which was
demonstrated to be osteoanabolic with an in vivo bone
formation rate (BFR) of 82% of DHT at 3 mg/kg, but little
to no ability to stimulate uterine weight in a 24-day in vivo
ovariectomized rat model (only 1% of uterine weight
[Nantermet et al., 2005]) in a 24-day in vivo
ovariectomized rat model (unpublished data).
Diaryl butanamides and carbonylamino-benzimidazoles
Merck scientists also patented two distinct diaryl SARM
templates, as shown in Figure 7 (43-45).The diaryl
butanamides (representative examples (43) and (44))
closely resemble the propionamides, but differ by the
quarternary carbon being ethyl substituted (making them
butanamides) and the insertion of a methylene group
between the A-ring and the amide. Points of variation
include the A-ring which can be pyridin-4-yl (World patent
application WO2007 016358 [Perkins et al., 2007]),
pyridin-3-yl (World patent application WO2006 060108
[Kim et al., 2006]), or benzyl (US patent application
US2005 277681 [Hanney et al., 2005]).
The tertiary carbon alkyl substituent can be methyl or
ethyl and perfluorinated or not. Also various A- and B-ring
substituents and substitution patterns have been explored.
The carbonylamino-benzimidazole (World patent
application WO2004 041277 [Kim et al., 2004]) template
has three basic variations: 1) diaryl benzimidazoles with
no linker (not shown), 2) urea+benzimidazole linked triaryl
compounds [representative example (45) shown in Figure
7], and 3) amide+benzimidazole linked triaryl compounds
(not shown).
Chromeno and quinolinyl benzazepines
Merck scientists patented a handful of anthracene-based
chromeno and quinolinyl benzazepines (representative
example (46) in Figure 7).These compounds are
reportedly SARMs that were tested by the same panel of
assays as for other Merck patents (supra); however no
activity is reported (US patent US 7,196,076 [Coleman
and Neilson, 2007]).
GlaxoSmithKline (GSK)
Disubstituted and diaryl anilines
GSK patents outline a wide variety of disubstituted aniline
templates to include para nitro/cyano and ortho/meta
electron withdrawing A-ring substituents on a phenyl
A-ring. Examples of the structural diversity of this series
are given in Figure 8 with the following compounds:
(47-48) (US patent application US2006 0148893 [Blanc
et al., 2006]), (49) (World patent application WO2005
000795 [Blanc et al., 2005]), (50) (World patent
application WO2005 085185 [Turnbull et al., 2005]),
(51-52) (World patent application WO2006 133216
[Turnbull et al., 2006]). Alternatively, these compounds
have para nitro/cyano naphthyl A-rings such as (53-54)
(US patent application US2006 0142387 [Cadilla et al.,
2006]).The aniline substituents of these templates include
alkyl, haloalkyl, alkenyl, cycloalkyl, alkanol, alkylamino,
and carboxylate and derivatives (Figure 8).The patents
describe GR, PR, MR, and AR binding affinity and
AR-luciferase transactivation in vitro assays and in vivo
studies in castrated rats analyzing VP and SV, LA and
bulbocavernosus (BC) muscles as androgenic and
anabolic indicators, respectively. However, the only GSK
disubstituted aniline for which biological data is disclosed
is a nilutamide-like cyclic aniline template [Trump et al.,
2007]. A virtual screening-guided combinatorial chemistry
approach was used to find AR agonists with various
substitutions of the left ring and various replacements of
the right ring, as shown, of compound (55).This yielded
352 submicromolar and 17 subnanomolar AR agonists,
as measured by a cell-based reporter gene functional
assay.
GSK scientists patented a series of diarylanilines which
are described as AR modulators, but did not disclose
biological activities other than ‘favorable’ compounds
have pIC50 (binding) <5 and LA hypertrophy with little
prostate stimulation (i.e., SARMs) (World patent
application WO2006 044707 [Turnbull et al., 2006]). A
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Review SARMs in development
Figure 7. SARM templates from Merck. Merck explored several templates, but focused the most effort on the 4-azasteroidal and the butanamide
scaffolds, for which they have multiple patents. Merck recently disclosed SARM activity for the first time for (42) at an ACS meeting. (42) was characterized
as osteoanabolic with low virilization potential in in vivo rat uterine growth assays (Nantermet et al., 2005).The structures for (43-46) were derived from
the indicated patent applications. BFR is an abbreviation for bone formation rate.
representative example (56) is given in Figure 8.
Structural variation included diaryl compounds similar to
bicalutamide, but separated by 3, 4, 5 or 6 atoms. Often
times, the anilido nitrogen was tertiary with a substituted
aliphatic side chain. Also, the linker chiral alcohol of
propionamides was replaced by a central amide separate
from the aniline.
Benzoxazepinones
At the 234th ACS National Meeting (Fall, 2007), Rafferty
et al. disclosed a structurally dissimilar template of
putative SARMs to include GSK8698 (57) and GSK4336A
(58) shown in Figure 8 which are benzoxazepinones with
an electron-deficient anilide side chain. In in vitro
analyses, these two representative examples are potent
agonists with variable half-lives (unpublished data).In
vivo activity is not known.
Preclinical and clinical SARMs (undisclosed structures)
At the 89th Annual Endocrine Society Meeting (June,
2007), Han et al. disclosed their first in vivo SARM
characterization. GSK2420A (structure not given)
demonstrated an ED50 (LA) of 0.026 mg/kg in a seven
day castrated rat model and restored castration-induced
LA muscle atrophy in a 28-day treatment.The effects of
GSK2420A on the prostate are consistent with partial
agonist activity, eliciting a 2-fold increase over vehicle
(versus 7-fold stimulation for DHT (3 mg/kg)), and
decreased prostate weight in intact rats (unpublished
data).
As reported on ClinicalTrials.gov (A service of the U.S.
National Institutes of Health) [NIH, 2008], the first clinical
candidate from GSK is GSK971086 (structure not
published) for which they are currently enrolling a Phase
I clinical trial to test the safety, tolerability, and blood
levels after 1 dose & 7 days of dosing in healthy adult
males.
Miscellaneous others
Eli Lilly and Company, Inc.
Lilly scientists patented two distinct SARM templates, the
N-arylpyrrolidines and the tetrahydrocarbazoles, along
with in vivo demonstrations of tissue-selective
myoanabolic activity.
Substituted N-arylpyrrolidines: Lilly scientists patented a
series of substituted N-arylpyrrolidines as a SARM
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Review SARMs in development
Figure 8. SARM templates from GlaxoSmithKline (GSK). GSK patented an assortment of aniline SARMs (47-54) without specific SARM
characterization, but rather just in vitro data.The aniline (55) was characterized in vitro as an AR agonist. Separately, GSK reported in conference
abstracts in vitro characterizations of benzoxazepines as AR agonists. GSK has reported their first public disclosure of SARM activity in a conference
abstract for GSK2420A (structure not known), and is pursuing GSK971086 (structure not known) as a clinical candidate. Although there is not much
public information from GSK, the breadth of their patents and presentations suggests that they have an active SARM program.
template (World patent application WO2006 124447
[Gavardinas et al., 2006]).In vitro activity was reported
for numerous compounds to achieve low nM AR binding
with several potent transcriptional activators that approach
full agonist efficacy in C2C12 cells as an indicator of
agonist activity in muscle tissue.The in vivo activity was
reported for two compounds (59) (reportedly commercially
available) and (60), which were tested in castrated (at 8
weeks) mice after 8 weeks of wasting (Figure 9).Test
animals were dosed over a two week timeframe at 0.3,
1, 3, 10, and 30 mg/kg per day by mouth (i.e., per os (po))
or subcutaneously (s.c.). Positive control animals were
dosed at 10 mg/kg daily with T enanthate. LA muscle was
used as the indicator of efficacy with % efficacy (treated
vs. vehicle-treated castrated animals) for (59) and (60)
of 186% (s.c.) and 164% (po) at 10 mg/kg per day,
respectively. Although no data was disclosed, these
compounds reportedly did not increase weights of SV or
prostate.The most active compounds are highly similar
in structure. Apparently, p-CN, m-Cl, o-Me substitution
of the A-ring (similar to BMS-564929 (29)) with an aryl R
substituent off an otherwise unsubstituted pyrrolidine
produces the most potent in vitro agonists, some of which
also have in vivo agonist activity in LA. Pfizer has also
reported SARM activity with a similar molecule ((62) in
Figure 9), an N-arylpiperidine described supra. Likewise,
GlaxoSmithKline has also reported similar compounds
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Review SARMs in development
such as (55) with reported in vitro agonist activity [Trump
et al., 2007] (Figure 8).
Tetrahydrocarbazole SARMs: Lilly scientists patented the
synthesis, binding affinity and transcriptional activation
(AR/ARE in C2C1 cells) of a large series of
tetrahydrocarbazoles, many of which were high affinity,
in vitro agonists (World patent application WO2007
002181 [Fales et al., 2007]). Additionally, several
compounds were characterized in the same in vivo mouse
model of efficacy in SV, VP, and LA tissues as discussed
above (i.e., % efficacy expressed as percent of castrated,
vehicle-treated control).The myoanabolic compound,
(61), supported 306% of LA in this model, and reportedly
showed no statistical weight change in SV or VP, as
compared to vehicle-treated castrated controls (data not
shown).This efficacy is in excess of that demonstrated
with the N-arylpyrrolidine template, but unfortunately these
values are hard to compare to SARMs from other groups,
due to a lack % efficacy versus intact control or
testosterone.
Pfizer – cyclic or disubstituted anilines
Pfizer scientists patented a series of high AR affinity (low
nM range) cyclic (62) or disubstituted (63) anilines (World
patent application WO2005 108351 [Gant et al., 2005]).
Compounds (62) and (63) displayed IC50 values of 5.2
nM and 1.1 nM in binding assays (Figure 9), respectively.
Compound (62) (10 mg/kg/d, s.c.) effectively reduced fat
mass (121 g vs. 121 g sham and 149 g for
ovariectomized) and increased LBM (319 g vs. 299 g
sham and 291 g ovariectomized). Similar results were
achieved with these compounds in aged (11 month old)
rats. Compound (62) increased BMC (11.9 mg/mm vs.
11.9 mg/mm for sham and 11.0 mg/mm for
ovariectomized), but had lesser effect on BMD (602
mg/cm3 vs. 672 mg/cm3 for sham and 593 mg/cm3 for
ovariectomized). Compounds (62) and (63) showed
tissue-selectivity in castrated immature male rats (25 days
old). Daily subcutaneous administration (30 mg/kg) of
(62) and (63) for 4 days retained 100% and 89% of LA
weight, respectively, but only 33% and 39% of VP weight,
as compared to DHT (10 mg/kg).
At the 27th Annual Meeting of the ASBMR (2005), Ke et
al. reported osteoanabolic SARM activity for CE-590
(structure unknown), (unpublished data). CE-590 is a
high affinity (IC50 = 16 nM) SARM in vivo. An 8-week
treatment schedule of CE-590 (30 mg/kg orally, twice per
day) significantly decreased prostate weight by 26% in
sham rats (acting as an AR antagonist), as compared to
66% increase for DHT-treated sham rats (agonist activity).
CE-590 completely prevented castration-induced
decreases in trabecular content, trabecular density,
cortical content, cortical area and cortical thickness and
increases in bone resorption and turnover. No SARM
clinical candidates are known for Pfizer.
Acadia Pharmaceuticals, Inc. – aminophenyl derivatives
Acadia patented a novel template for SARMs involving
typical A-rings, but the aniline component is a [3.2.1]
tricyclic ring system, similar to some of the BMS
templates. Acadia reported compounds with modest
potency in terms of in vitro transcriptional agonist activity
(mid to high nM range) with efficacies ranging from 41%
to 94% (World patent application WO2005 115361
[Schlienger et al., 2005]). Compound 154BG31 ((64) in
Figure 9) produced significant increases in VP, SV, and
LA as compared to vehicle. LA weight was approximately
60% at a dose of 30 mg/kg, as compared to testosterone
propionate (1 mg/kg), whereas VP was approximately
20%.This represents ∼3-fold tissue-selectivity, but only
partial myoanabolic agonism. 154BG31 (64) also fully
suppressed LH at a dose of 10 mg/kg, which is in the
same range as myoanabolic activity, possibly limiting the
utility of these compounds for muscle indications.
Compound 198RL26 (65) was separately reported to be
a high affinity ligand (79% with an in vitro potency of
pEC50 = 8.8) and was selected for in vivo
experimentation. Like 154BG31, 198RL26 (65) is an in
vivo partial myoanabolic agonist of similar potency and
efficacy, and produced a dose-dependent suppression
of plasma LH levels such that a complete reversal was
evident at 10 mg/kg, suggesting CNS penetration (US
patent application US2006 0160845 [Schlienger et al.,
2006]). Acadia also reported ACP-105 (structure
unknown) as a SARM development candidate that has
reversed endocrine and bone-related markers of
testosterone deficiency in preclinical animal testing, with
little effect on the prostrate (unpublished data).
Summary of the SARM field
The development space for SARMs is becoming more
crowded with more in vivo characterizations of diverse
structural templates emerging at an accelerating pace.
Several groups have produced clinical candidate SARMs
to include: GTx, Inc. (OstarineTM for cachexia in Phase
II, structures not published), Bristol-Myers Squibb
(BMS-564929 (29) for age-related functional decline in
Phase I), and Ligand Pharmaceuticals, Inc. (LGD2941
(15) for frailty and osteoporosis in Phase I, and LGD2226
(14), which has been discontinued), and GlaxoSmithKline
(GSK971086) in dose finding Phase I studies, with more
clinical candidates likely to emerge in the near future. Not
surprisingly, some of these groups have published the
most detailed characterizations of their SARMs to include
S-1 (see literature for structure) and S-4 (6) (and many
others) from GTx, Inc.; BMS-564929 (29) from BMS;
LGD2226 (14) and LGD2941 (15) and others from Ligand.
The salient features for promising clinical and preclinical
SARMs include hypermyoanabolic and
hyperosteoanabolic efficacy (hyper-defined as in excess
of intact control) at doses associated with decreased
prostate size and little to no suppression of pituitary
gonadotropins. Others, such as (18-19) from Kaken and
S-1 from GTx, have demonstrated partial agonist activity
in prostate with potential in retarding growth of the
prostate, while retaining agonist effects in anabolic
tissues.The utility of the various SARMs in patients is
yet to be proven, but indeed seems very promising, given
the multitude of in vivo pre-clinical characterizations by
many groups, and the auspicious proof of concept results
for OstarineTM in Phase II clinical trials (discussed supra).
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Figure 9. SARMs patented by Lilly, Pfizer, and Acadia. Lilly patented two SARM templates, the N-arylpyrrolidines and tetrahydrocarbazoles,
which they characterize as tissue-selective. Unfortunately, their comparisons are to vehicle-treated animals, making it hard to assess the relative activity
compared to other templates. Pfizer likewise has patented an aniline series of SARMs, which they characterize as high affinity and tissue-selective full
agonists. Acadia too has patented a novel SARM template of [3.2.1] tricyclic anilines, which they characterize as weak anabolic agents that suppress
LH at therapeutic doses.
These and other in vivo characterizations of SARMs are
summarized in Supplementary File 1.
Knowledge of SARM interactions with
the AR
X-ray crystallography has elucidated binding modes of a
number of the above-mentioned SARMs.The crystal
structure of the AR LBD was first described by Matias et
al. in 2000 in a complex with the synthetic steroid, R1881
[Matias et al., 2000].The first SARM-bound AR crystal
structure, reported in 2005, was with the bicalutamide
derivative, S-1 [Bohl et al., 2005b].Whereas helix 12 of
the ERα LBD adopts an alternate conformation when
comparing estradiol and SERM (i.e., tamoxifen and
raloxifene)-bound structures, the protein fold of the
SARM-bound AR LBD and steroidal-agonist bound (e.g.,
R1881, DHT) are the same [Bohl et al., 2005b;
Brzozowski et al., 1997; Matias et al., 2000; Sack et al.,
2001;Tanenbaum et al., 1998;Wang et al., 2006].This
finding has held true for all SARM-bound AR LBD x-ray
crystal structures published to date (Figure 10a).Thus,
a structural basis for the mechanism of SARM activity
was not made apparent through the use of x-ray
crystallography. However, information regarding the
binding modes of the various nonsteroidal
pharmacophores complexed to the AR provides
information for rational drug design (Figure 10).
Additionally, the different receptor interactions when
comparing steroidal agonists and nonsteroidal SARMs
may play a role in altering the protein conformation in
solution.
Until S-1 binding mode was solved, it was unknown how
the AR could accommodate aryl propionamide SARMs.
Various modeling studies proposed alternate areas in the
AR binding pocket where the B-ring was positioned [Bohl
et al., 2004; Salvati et al., 2005a; Soderholm et al., 2005].
Each of these molecular models was based on theoretical
flexible regions of the AR, as the binding pocket in the
steroidal-bound crystal structures was not of adequate
size to accommodate the bulk of such analogs.The x-ray
crystal structure of the S-1-AR LBD complex elucidated
that the W741 side chain is displaced by the B-ring to
expand the binding pocket such that the compound bends
90° and orients towards the AF-2 region [Bohl et al.,
2005b] (Figure 10c).The fluorine on the para position of
the B-ring appears to act as a hydrogen bond acceptor
to a conserved water molecule that is stabilized by the
H874 side chain and backbone of helices 4 and 5,
explaining the increased potency of compounds with
cyano and nitro substitutions at this position [Kim et al.,
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Figure 10. X-ray crystal structures of the AR LBD with DHT and SARMs. (a) The general protein fold of the AR LBD-DHT complex (PDB code
1i37) superimposed with binding conformations of nonsteroidal SARMs including S-1 from GTx (green, PDB code 2axa), LGD2226 from Ligand
Pharmaceuticals (pink, PDB code 2hvc), and ‘10b’ from BMS (purple, PDB code 2ihq) shows how the compounds are accommodated within the agonist
form of the AR LBD. Oxygen-red; nitrogen-blue, sulfur-orange; fluorine-cyan. (b) Bound conformation of DHT shows hydrogen bonds between the
3-keto group and R752, as well as the 17α-hydroxyl group with N705 and T877. (c) The A-ring nitro group of S-1 interacts with R752 similar to the
3-keto group of DHT, while the amide NH and hydroxyl groups form hydrogen bonds to L704 and N705, respectively.The B-ring of S-1 orients towards
the AF-2 by displacing W741 and the p-fluorine of the B-ring forms a water-mediated hydrogen bond to H874. (d) LGD2226 binds similar to DHT with
the ketone on the A-ring hydrogen bonding to R752, but contains an additional hydrogen bond to Q711 through its heterocyclic A-ring. (e) 10b forms
hydrogen bonds to R752 and N705 with increased hydrophobic contacts as a result of its bicyclic ring systems.
2005]. Similar to the steroidal androgens R1881 and DHT
(Figure 10b), hydrogen bonding occurs with R752 and
Q711 to the A-ring nitro group, and N705 to the hydroxyl
group of S-1. However, unlike steroidal binding, no
hydrogen bond to T877 occurs. Given the close chemical
structures of S-1 and R-bicalutamide, it became clear
from the S-1-bound AR LBD structure as to why the two
compounds exhibited different activities (i.e., agonist vs.
antagonist). A sulfonyl linkage on R-bicalutamide in place
of the ether linkage of S-1 would be poorly accommodated
in the agonist fold of the AR LBD.While it had been
shown that R-bicalutamide induces an agonist fold in the
W741L mutant AR LBD through x-ray crystallography
[Bohl et al., 2005a], the sulfonyl group of R-bicalutamide
would result in steric clash between W741 and M895 in
the wt AR, thus precluding the conformation seen in the
S-1- and steroid-bound structures.To date, no structure
of an antagonist-bound wt AR LBD has been reported.
Ligand Pharmaceuticals published a crystal structure of
LGD2226, a bicyclic hydantoin SARM bound to the AR
LBD in 2006 [Wang et al., 2006].This structure exhibited
interesting interactions including a repositioning of Q711
to form a hydrogen bond with both the carbonyl and
secondary amine of the A ring, as well as a hydrogen
bond to R752 (Figure 10d). Favorable contacts with the
two branched trifluoromethyl groups were observed.While
there were no apparent hydrogen bonds to N705 or T877,
van der Waals interactions with the trifluoromethyl groups
and these residues may play a role in this compound's
high affinity. Unlike aryl propionamide SARMs, this
compound does not expand to the binding pocket relative
to R1881- and DHT-bound AR.
Bristol-Myers Squibb (BMS) published their first crystal
structure of a SARM bound to the wt AR LBD in 2006
[Sun et al., 2006] (Figure 10e). It demonstrated how a
compound similar to BMS-564929 (29), a derivative of
the antiandrogen nilutamide containing two fused
five-membered rings binds the AR. Similar to aryl
propionamide SARMs, this compound forms a hydrogen
bond to N705 and not T877.
Plausible mechanisms for tissue
selectivity of SARMS
The importance of androgens is not appreciated until
post-andropause diseases such as osteoporosis,
cachexia and others develop.Though administration of
steroidal androgens improves muscle mass and bone
mineral density, they also have undesired effects leading
to increased prostate size, acne, effects on serum lipids
and others.The greatest challenge in the discovery of
SARMs was to separate the androgenic (effect on
secondary sexual organs) and anabolic effects (effects
on muscle and bone). Many have now shown successfully
in preclinical models and in clinical trials that the SARMs
efficiently separate the androgenic and anabolic effects
[Chen et al., 2005c; Gao and Dalton, 2007; Kearbey et
al., 2007]. How this separation is achieved by SARMs,
almost identical to SERMs, is complex and still under
investigation.Though 10 years have elapsed since the
discovery of the first SARM, the proposed mechanisms
for SARM action have been adopted from SERMs.
The proposed mechanisms for the tissue selectivity of
SARMs include the role of 5α-reductase, tissue-specific
expression of coregulators, differences in the complexes
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formed by AR in anabolic and androgenic tissues, and
the tissue-specific role of intracellular signaling cascades.
5α-reductase and aromatase
SARMs developed to date are resistant to 5α-reduction
or aromatization.This is considered as at least one
plausible contributing factor for the tissue selectivity of
SARMs [Buijsman et al., 2005].The most active androgen
in prostate is DHT, which is formed by the 5α-reduction
(5-α-reductase is expressed in prostate and skin) of
testosterone, the most abundant circulating androgen.
Inhibition of 5α-reductase by finasteride leads to inhibition
of prostate size without any effect on muscle or bone
mass, indicating that the lack of 5α-reduction of
testosterone separates the prostate from muscle or bone
effects [Wright et al., 1999]. More importantly,
5α-reductase is expressed in high levels in prostate, but
at very low levels in bone or muscle, which explains the
significance of DHT in prostate and testosterone in muscle
and bone function. As SARMs lack interaction with
5α-reductase, this is considered a logical explanation for
at least some of their tissue selectivity.
Another enzyme that plays a pivotal role in androgen
metabolism is aromatase, the enzyme that converts
testosterone to estradiol.This enzymatic reaction has
been shown to be very critical for several physiological
and pathological processes. Aromatase is ubiquitously
expressed throughout the male reproductive tract,
indicating that local conversion of testosterone to estradiol
increases the prostate growth [Matzkin and Soloway,
1992;Tsugaya et al., 1996]. Estradiol increases the
prostate size and predisposes men to prostate cancer.
Testosterone, the aromatizable androgen, increases the
prostate size, both through conversion to estradiol and
DHT. SARMs cannot be aromatized, conferring all their
effects to AR binding and not to metabolic conversion to
active androgens/estrogens in prostate.
Coregulator function
The functions of AR and its family members are
dependent on the expression of associated proteins called
coregulators.These coregulators do not bind to the DNA,
but are recruited to the DNA by hormone bound receptors,
enhancing (coactivators) or reducing (corepressor) the
AR transactivation. In total, around 300 coregulators have
been identified as belonging to several classes that play
a pivotal role in AR function. Readers are referred to other
excellent reviews on coregulators for more information
[Smith and O'Malley, 2004].
AR differs from other receptors in its interactions with
coregulators.The LBD of AR and other nuclear receptors
have 12 anti-parallel helices that undergo significant
rearrangement upon ligand binding, creating a shallow
hydrophobic pocket containing LxxLL motif to facilitate
association with coactivators [Heery et al., 1997; Shiau
et al., 1998]. However, in AR most of the coactivators
bind to a LxxLL motif in AF-1 domain and some bind to
the LxxLL motifs in AF-2 domain [He et al., 2002a;
Heinlein and Chang, 2002]. Activated AR also appears
to bind strongly and specifically to unusual FxxFF and
FxxFM motifs in a subgroup of LBD-binding cofactors
such as gelsolin and PAK6 [van de Wijngaart et al., 2006].
Moreover, there are several proteins that exclusively
coactivate AR (ARA family of coactivators) and are not
shared by other receptors [Fujimoto et al., 1999; Kang et
al., 1999].
Conformational differences induced by SARMs lead to
association and recruitment of different coregulator
complexes [Chang and McDonnell, 2002]. Using
combinatorial peptide-phage display, McDonnell and his
colleagues showed that different ligands induce distinct
AR and ER conformations leading to their association
with different coactivator peptides [Chang et al., 1999;
Chang and McDonnell, 2002].The SARMs RTI-018 and
RTI-001 possessed a spectrum of agonist activities and
altered kinetics of response and these differences were
attributed to SARM-mediated structural differences
leading to the association of SARM-AR with coactivator
peptides distinct from the DHT-AR complex [Kazmin et
al., 2006].
Another study in support of the above conclusion was
published recently by Rosenfeld and his colleagues [Baek
et al., 2006].This study was performed to provide a
mechanism for the agonist effect of bicalutamide in the
presence of an activated IL-8 pathway. As an antagonist,
bicalutamide recruited corepressors NCoR and SMRT
and as an agonist, in the presence of IL-8, the same
ligand recruited p160 coactivators.This study also
demonstrates that of the 3 LxxLL helices (LXDs) in the
receptor interacting domain of SRC-1, DHT required LXD1
and LXD2, whereas SARM-mediated action required
LXD2 and LXD3 [McInerney et al., 1998].
Based on the above-provided and other literature
information, SARMs possibly recruit coactivator
complexes similar to DHT in anabolic tissues and
corepressor complexes in androgenic tissues. Another
possibility is that the SARMs, in androgenic tissues, might
recruit a complex containing both coactivators and
corepressors, leading to weaker agonist properties. All
of the above-proposed mechanisms need to be addressed
in appropriate animal models.
Intracellular signaling cascades
The identity of the pathways impacted by androgen in a
given cell is a function of both AR-dependent and
AR-independent criteria. AR ligands affect different
signaling pathways in different cells to elicit their effects.
A classical example is that testosterone signals through
inhibition of p38 MAPK, Notch-1, Notch-2 and Jagged-1
signaling pathways in macrophages.Whereas
testosterone signals through activation of PI3K-Akt
pathways in bone cells [Guo et al., 2004; Kang et al.,
2004; Liu et al., 2006]. However, androgens did not inhibit
p38 MAPK in bone cells, corroborating the fact that the
same ligand impacts diverse pathways, depending on
cell and tissue type, to mediate the physiological response
[Huber et al., 2001].
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Binding of ligand to AR leads to posttranslational
modifications of receptors and their associated proteins,
which occur in a pathway-specific manner. One of the
important posttranslational modifications that plays a
critical role in receptor and coregulator function is
phosphorylation. Depending on the cell type, upon
tamoxifen binding to ER, the receptor is specifically
phosphorylated, which in turn alters the ligand and DNA
binding functions of ER and coregulators [Likhite et al.,
2006]. AR phosphorylation is also affected
ligand-dependently and -independently through growth
factor alteration, leading to divergent physiological
responses [Dehm and Tindall, 2006].
The role of non-genomic effects (an evolving field of
study) in androgen and estrogen signaling is still
conflicting. Manolagas and his colleagues demonstrated
that non-genomic signaling is important for the bone
protective effects of androgens and estrogens, whereas
genomic effects are critical for the development of sexual
organs [Kousteni et al., 2001]. Separation of these two
pathways by SARMs leads to increase in bone mass,
with no effect on sexual organs.Testosterone and
androstenedione, but not DHT and the synthetic androgen
R1881, mediate non-genomic effects in mature Xenopus
laevis oocytes. However, evidence from other laboratories
has also implicated a role for this non-genomic signaling
in the development and pathology of sexual organs. Lutz
et al. suggested the development of SARMs that
selectively impact non-genomic pathways could be used
therapeutically for polycystic ovarian syndrome [Lutz et
al., 2003]. More studies are required to evaluate the role
of non-genomic signaling in androgen and estrogen
biology.
Unlike the role of coactivators, several animal studies
validated the role of genomic and non-genomic signaling
in physiological responses and correlated with responses
obtained with different ligands. However, all these
validations were done with native ligands and hence have
to be extended to SARMs.
Conclusions
The AR has recently undergone a renaissance as a
therapeutic target with the emergence of a new class of
potential therapeutic agents (i.e., SARMs). Major
milestones along the road include the discovery of
nonsteroidal AR ligands (antiandrogens) in the 1970s
with flutamide, improvement of the pharmacokinetic
characteristics resulting in bicalutamide in the 1980s, and
the conversion of antagonist to agonist templates in the
late 1990s serving as seminal events that defined the
field of SARMs.These events served as a tremendous
catalyst for the exploration of AR ligands with SARM
activity; a field that expanded from two small groups
(University of Tennessee Health Science Center and
Ligand Pharmaceuticals, Inc.) to encompass many of the
major players (BMS, GSK, J&J, Lilly, Merck, etc.) in the
pharmaceutical industry.
Deeper analysis of the in vivo activity profiles achieved
by SARMs suggests a promising outlook. AR is the only
target which concurrently addresses bone and muscle
weakness, and the improved PK/PD profiles of SARMs,
as presented herein relative to FDA-approved steroidal
agonists, bodes well for this class as the next generation
of androgen therapy. Also SARMs, as osteo- and
myoanabolic agents, have the potential to achieve the
status of anabolic-agent-of-choice for many conditions
that only require osteo- or myoanabolic effects, since the
(side) effect in the untreated tissue is beneficial and
synergistic.
The relatively recent proof-of-principle clinical trials
demonstrating potent anabolic effects in humans was a
valuable observation that sets the stage for exploration
of the many clinical applications of an agent with
unprecedented osteo- and myoanabolic activity. The rapid
advancement of the SARM field in terms of chemotype
diversity, mechanistic understanding, and information
gleaned from the multiple SARMs in the clinic will help to
define the ideal pharmacologic profiles for various
potential indications under investigation. Already,
auspicious preliminary clinical reports suggest that
SARMs are a class of promising preclinical and clinical
candidates. As this trend continues, many of the clinical
and regulatory challenges with SARMs will be addressed
and overcome, and hopefully, the full potential of SARMs
as a class of promising preclinical and clinical candidates
will be realized. If the full potential that is embodied in
this class is realized, SARMs will force a paradigm shift
in the treatment of patients requiring anabolic therapy.
Supplementary Material
Supplementary File 1: In vivo characterizations of
tissue-selective androgen receptor modulators.
References
Alen, P., Claessens, F., Verhoeven, G., Rombauts, W. and Peeters, B.
(1999) The androgen receptor amino-terminal domain plays a key role in
p160 coactivator-stimulated gene transcription Mol Cell Biol 19, 6085-97.
Allan, G., Lai, M.T., Sbriscia, T., Linton, O., Haynes-Johnson, D.,
Bhattacharjee, S., Dodds, R., Fiordeliso, J., Lanter, J., Sui, Z. and
Lundeen, S. (2007b) A selective androgen receptor modulator that reduces
prostate tumor size and prevents orchidectomy-induced bone loss in rats
J Steroid Biochem Mol Biol 103, 76-83.
Allan, G. F., Tannenbaum, P., Sbriscia, T., Linton, O., Lai, M. T.,
Haynes-Johnson, D., Bhattacharjee, S., Zhang, X., Sui, Z. and Lundeen,
S. G. (2007a) A selective androgen receptor modulator with minimal
prostate hypertrophic activity enhances lean body mass in male rats and
stimulates sexual behavior in female rats Endocrine 32, 41-51.
Allan, G. F. and Sui, Z. (2003) Therapeutic androgen receptor ligands
Nucl Recept Signal 1, e009.
Araujo, A. B., Esche, G. R., Kupelian, V., O'Donnell, A. B., Travison, T.
G., Williams, R. E., Clark, R.V. and McKinlay, J. B. (2007) Prevalence
of symptomatic androgen deficiency in men J Clin Endocrinol Metab 92,
4241-7.
Baek, S. H., Ohgi, K. A., Nelson, C. A., Welsbie, D., Chen, C., Sawyers,
C. L., Rose, D. W. and Rosenfeld, M. G. (2006) Ligand-specific allosteric
regulation of coactivator functions of androgen receptor in prostate cancer
cells Proc Natl Acad Sci U S A 103, 3100-5.
Bahnson, R. (2007) Androgen deprivation therapy for prostate cancer J
Urol 178, 1148.
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06010 | Page 20 of 26
Review SARMs in development
Balog, A., Salvati, M. E., Shan, W., Mathur, A., Leith, L.W., Wei, D. D.,
Attar, R. M., Geng, J., Rizzo, C. A., Wang, C., Krystek, S. R., Tokarski,
J. S., Hunt, J.T., Gottardis, M. and Weinmann, R. (2004) The synthesis
and evaluation of [2.2.1]-bicycloazahydantoins as androgen receptor
antagonists Bioorg Med Chem Lett 14, 6107-11.
Batterham, M. J. and Garsia, R. (2001) A compar ison of megestrol acetate,
nandrolone decanoate and dietary counselling for HIV associated weight
loss Int J Androl 24, 232-40.
Bevan, C. L., Hoare, S., Claessens, F., Heery, D. M. and Parker, M. G.
(1999) The AF1 and AF2 domains of the androgen receptor interact with
distinct regions of SRC1 Mol Cell Biol 19, 8383-92.
Blanc, J. E., Cadilla, R., Cowan, D. J., Kaldor, I., Larkin, A. L., Stewart,
E. L., Turnbull, P. S. and Trump, R. P. (2005) Aniline derivatived
androgen-, glucocorticoid-, mineralcorticoid- and progesterone- receptor
modulators WO2005 000795.
Blanc, J. B., Cadilla, E., Cowan, R., Kaldor, D. J., Larkin, I., Stewart, A.
L., Trump, E. L. and Turnbull, R. P. (2006) Chemical compounds US2006
0148893.
Blumberg, B. and Evans, R. M. (1998) Orphan nuclear receptors--new
ligands and new possibilities Genes Dev 12, 3149-55.
Bocklandt, S. and Vilain, E. (2007) Sex differences in brain and behavior:
hormones versus genes Adv Genet 59, 245-66.
Bohl, C. E., Chang, C., Mohler, M. L., Chen, J., Miller, D. D., Swaan, P.
W. and Dalton, J. T. (2004) A ligand-based approach to identify
quantitative structure-activity relationships for the androgen receptor J
Med Chem 47, 3765-76.
Bohl, C. E., Miller, D. D., Chen, J., Bell, C. E. and Dalton, J.T. (2005a)
Structural Basis for Accommodation of Nonsteroidal Ligands in the
Androgen Receptor J Biol Chem 280, 37747-37754.
Bohl, C. E., Gao, W., Miller, D. D., Bell, C. E. and Dalton, J.T. (2005b)
Structural basis for antagonism and resistance of bicalutamide in prostate
cancer Proc Natl Acad Sci U S A 102, 6201-6.
Brooke, G. N., Parker, M. G. and Bevan, C. L. (2008) Mechanisms of
androgen receptor activation in advanced prostate cancer: differential
co-activator recruitment and gene expression Oncogene 27, 2941-50.
Brzozowski, A. M., Pike, A. C., Dauter, Z., Hubbard, R. E., Bonn, T.,
Engstrom, O., Ohman, L., Greene, G. L., Gustafsson, J. A. and Carlquist,
M. (1997) Molecular basis of agonism and antagonism in the oestrogen
receptor Nature 389, 753-8.
Buijsman, R. C., Hermkens, P. H., van Rijn, R. D., Stock, H.T. and
Teerhuis, N. M. (2005) Non-steroidal steroid receptor modulators Curr
Med Chem 12, 1017-75.
Cadilla, R., Larkin, A. L., Stewart, E. L., Trump, R. P. and Turnbull, P. S.
(2006b) Chemical compounds US2006 0142387 .
Cadilla, R. and Turnbull, P. (2006a) Selective androgen receptor
modulators in drug discovery: medicinal chemistry and therapeutic
potential Curr Top Med Chem 6, 245-70.
Cardozo, C. P., Michaud, C., Ost, M. C., Fliss, A. E., Yang, E., Patterson,
C., Hall, S. J. and Caplan, A. J. (2003) C-terminal Hsp-interacting protein
slows androgen receptor synthesis and reduces its rate of degradation
Arch Biochem Biophys 410, 134-40.
Chang, C., Norris, J. D., Gron, H., Paige, L. A., Hamilton, P.T., Kenan,
D. J., Fowlkes, D. and McDonnell, D. P. (1999) Dissection of the LXXLL
nuclear receptor-coactivator interaction motif using combinatorial peptide
libraries: discovery of peptide antagonists of estrogen receptors α and β
Mol Cell Biol 19, 8226-39.
Chang, C.Y. and McDonnell, D. P. (2002) Evaluation of ligand-dependent
changes in AR structure using peptide probes Mol Endocrinol 16, 647-60.
Chen, J., Hwang, D. J., Bohl, C. E., Miller, D. D. and Dalton, J.T. (2005b)
A selective androgen receptor modulator for hormonal male contraception
J Pharmacol Exp Ther 312, 546-53.
Chen, J., Kim, J. and Dalton, J.T. (2005c) Discovery and therapeutic
promise of selective androgen receptor modulators Mol Interv 5, 173-88.
Chen, J., Hwang, D. J., Chung, K., Bohl, C. E., Fisher, S. J., Miller, D. D.
and Dalton, J.T. (2005a) In vitro and in vivo structure-activity relationships
of novel androgen receptor ligands with multiple substituents in the B-ring
Endocrinology 146, 5444-54.
Clay, C. A., Perera, S., Wagner, J. M., Miller, M. E., Nelson, J. B. and
Greenspan, S. L. (2007) Physical function in men with prostate cancer
on androgen deprivation therapy Phys Ther 87, 1325-33.
Coleman, P. J. and Neilson, L. A. (2007) Androgen receptor modulators
and methods of use thereof US 7,196,076.
Dalton, J.T. (2007a) Development and Potential Uses of Selective
Androgen Receptor Modulators (SARMs) American Society of Andrology
Dalton, J.T., Mukherjee, A., Zhu, Z., Kirkovsky, L. and Miller, D. D. (1998)
Discovery of nonsteroidal androgens Biochem Biophys Res Commun
244, 1-4.
Dalton, J.T. (2007b) Therapeutic Promise of Selective Androgen Receptor
Modulators (SARMs): Preclinical and Clinical Proof-of-Concept Studies.
Annual Meeting of The Endocrine Society, Abstract #S41-2.
Dankulich, W. P., Kaufman, M. L., Meissner, R. S. and Mitchell, H. J.
(2006) 17-Acetamido-4-azasteroid derivatives as androgen receptor
modulators US2006 0258661.
Dankulich, W. P., Kaufman, M. L., Meissner, R. S. and Mitchell, H. J.
(2005a) 17-Acetamido-4-azasteroid derivatives as androgen receptor
modulators WO2005 0005606.
Dankulich, W. P., Meissner, R. S. and Mitchell, H. J. (2005b)
17-Acetamido-4-azasteroid derivatives as androgen receptor modulators
WO2005 004807.
Dankulich, W. P., Meissner, R. S. and Mitchell, H. J. (2005)
17-Acetamido-4-azasteroid derivatives as androgen receptor modulators
WO2005 009949.
De Marzo, A. M., Platz, E. A., Sutcliffe, S., Xu, J., Gronberg, H., Drake,
C. G., Nakai, Y., Isaacs, W. B. and Nelson, W. G. (2007) Inflammation in
prostate carcinogenesis Nat Rev Cancer 7, 256-69.
Dehm, S. M. and Tindall, D. J. (2007) Androgen receptor structural and
functional elements: role and regulation in prostate cancer Mol Endocrinol
21, 2855-63.
Dehm, S. M. and Tindall, D. J. (2006) Ligand-independent androgen
receptor activity is activation function-2-independent and resistant to
antiandrogens in androgen refractory prostate cancer cells J Biol Chem
281, 27882-93.
Dolan, S. E., Carpenter, S. and Grinspoon, S. (2007) Effects of weight,
body composition, and testosterone on bone mineral density in
HIV-infected women J Acquir Immune Defic Syndr 45, 161-7.
Edwards, J. P., Higuchi, R. and Jones, T. (2000) Androgen receptor
modulator compounds and methods US 2000 6,017,924.
Edwards, J. P., West, S. J., Pooley, C. L., Marschke, K. B., Farmer, L. J.
and Jones, T. K. (1998) New nonsteroidal androgen receptor modulators
based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone Bioorg
Med Chem Lett 8, 745-50.
Edwards, J. P., Higuchi, R. I., Winn, D.T., Pooley, C. L., Caferro, T. R.,
Hamann, L. G., Zhi, L., Marschke, K. B., Goldman, M. E. and Jones, T.
K. (1999) Nonsteroidal androgen receptor agonists based on
4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one Bioorg Med Chem Lett
9, 1003-8.
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06010 | Page 21 of 26
Review SARMs in development
Epstein, S. (2006) Update of current therapeutic options for the treatment
of postmenopausal osteoporosis Clin Ther 28, 151-73.
Escriva, H., Safi, R., Hanni, C., Langlois, M. C., Saumitou-Laprade, P.,
Stehelin, D., Capron, A., Pierce, R. and Laudet, V. (1997) Ligand binding
was acquired during evolution of nuclear receptors Proc Natl Acad Sci U
S A 94, 6803-8.
Ettinger, B., Black, D. M., Mitlak, B. H., Knickerbocker, R. K., Nickelsen,
T., Genant, H. K., Christiansen, C., Delmas, P. D., Zanchetta, J. R.,
Stakkestad, J., Gluer, C. C., Krueger, K., Cohen, F. J., Eckert, S., Ensrud,
K. E., Avioli, L.V., Lips, P. and Cummings, S. R. (1999) Reduction of
vertebral fracture risk in postmenopausal women with osteoporosis treated
with raloxifene: results from a 3-year randomized clinical trial. Multiple
Outcomes of Raloxifene Evaluation (MORE) Investigators Jama 282,
637-45.
Evans, R. M. (1988) The steroid and thyroid hormone receptor superfamily
Science 240, 889-95.
Fales, K. R., Green, J.E., Jadhav, P. K., Matthews, D. P., Neel, D. A. and
Smith, E. C. R. (2007) Tetrahydrocarbazole derivatives useful as androgen
receptor modulators WO2007 002181.
Fang, Y., Fliss, A. E., Robins, D. M. and Caplan, A. J. (1996) Hsp90
regulates androgen receptor hormone binding affinity in vivo J Biol Chem
271, 28697-702.
Fisher, J. E., Rogers, M. J., Halasy, J. M., Luckman, S. P., Hughes, D.
E., Masarachia, P. J., Wesolowski, G., Russell, R. G., Rodan, G. A. and
Reszka, A. A. (1999) Alendronate mechanism of action: geranylgeraniol,
an intermediate in the mevalonate pathway, prevents inhibition of
osteoclast formation, bone resorption, and kinase activation in vitro Proc
Natl Acad Sci U S A 96, 133-8.
Frisoli, A., Jr., Chaves, P. H., Pinheiro, M. M. and Szejnfeld, V. L. (2005)
The effect of nandrolone decanoate on bone mineral density, muscle
mass, and hemoglobin levels in elderly women with osteoporosis: a
double-blind, randomized, placebo-controlled clinical trial J Gerontol A
Biol Sci Med Sci 60, 648-53.
Fujimoto, N., Yeh, S., Kang, H. Y., Inui, S., Chang, H. C., Mizokami, A.
and Chang, C. (1999) Cloning and characterization of androgen receptor
coactivator, ARA55, in human prostate J Biol Chem 274, 8316-21.
Furr, B. J. and Tucker, H. (1996) The preclinical development of
bicalutamide: pharmacodynamics and mechanism of action Urology 47,
13-25; discussion 29-32.
Gant, T. G., Hill, R. J., Ke, H. Z., Lefker, B. A. and O'Malley, J. P. (2005)
Benzonitrile derivatives to treat musculoskeletal frailty WO2005 108351.
Gao, W., Kearbey, J. D., Nair, V. A., Chung, K., Parlow, A. F., Miller, D.
D. and Dalton, J.T. (2004) Comparison of the pharmacological effects
of a novel selective androgen receptor modulator, the 5alpha-reductase
inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats:
new approach for benign prostate hyperplasia Endocrinology 145, 5420-8.
Gao, W. and Dalton, J. T. (2007) Expanding the therapeutic use of
androgens via selective androgen receptor modulators (SARMs) Drug
Discov Today 12, 241-8.
Gao, W., Reiser, P. J., Coss, C. C., Phelps, M. A., Kearbey, J. D., Miller,
D. D. and Dalton, J.T. (2005) Selective androgen receptor modulator
treatment improves muscle strength and body composition and prevents
bone loss in orchidectomized rats Endocrinology 146, 4887-97.
Gao, T., Marcelli, M. and McPhaul, M. J. (1996) Transcriptional activation
and transient expression of the human androgen receptor J Steroid
Biochem Mol Biol 59, 9-20.
Gavardinas, K., Jadhav, P. K., Stack, D. R. and Clemens, I. R. (2006)
Substituted N-arylpyrrolidines as selective androgen receptor modulators
WO2006 124447.
Gioeli, D., Black, B. E., Gordon, V., Spencer, A., Kesler, C.T., Eblen, S.
T., Paschal, B. M. and Weber, M. J. (2006) Stress kinase signaling
regulates androgen receptor phosphorylation, transcription, and
localization Mol Endocrinol 20, 503-15.
Goldberg, R. M., Loprinzi, C. L., Mailliard, J. A., O'Fallon, J. R., Krook, J.
E., Ghosh, C., Hestorff, R. D., Chong, S. F., Reuter, N. F. and Shanahan,
T. G. (1995) Pentoxifylline for treatment of cancer anorexia and cachexia?
A randomized, double-blind, placebo-controlled trial J Clin Oncol 13,
2856-9.
Grinspoon, S., Corcoran, C., Parlman, K., Costello, M., Rosenthal, D.,
Anderson, E., Stanley, T., Schoenfeld, D., Burrows, B., Hayden, D.,
Basgoz, N. and Klibanski, A. (2000) Effects of testosterone and
progressive resistance training in eugonadal men with AIDS wasting. A
randomized, controlled trial Ann Intern Med 133, 348-55.
Guo, D., Zhang, H., Liu, L., Wang, L., Cheng, Y. and Qiao, Z. (2004)
Testosterone influenced the expression of Notch1, Notch2 and Jagged1
induced by lipopolysaccharide in macrophages Exp Toxicol Pathol 56,
173-9.
Hair, W. M., Kitteridge, K., O'Connor, D. B. and Wu, F. C. (2001) A novel
male contraceptive pill-patch combination: oral desogestrel and
transdermal testosterone in the suppression of spermatogenesis in normal
men J Clin Endocrinol Metab 86, 5201-9.
Hamann, L. G., Mani, N. S., Davis, R. L., Wang, X. N., Marschke, K. B.
and Jones, T. K. (1999) Discovery of a potent, orally active, nonsteroidal
androgen receptor agonist: 4-ethyl-1,2,3,4-tetrahydro-6-
(trifluoromethyl)-8-pyridono[5,6-g]- quinoline J Med Chem 42, 210-2.
Hamann, L. G., Manfredi, M. C., Sun, C., Krystek, S. R., Jr., Huang, Y.,
Bi, Y., Augeri, D. J., Wang, T., Zou, Y., Betebenner, D. A., Fura, A.,
Seethala, R., Golla, R., Kuhns, J. E., Lupisella, J. A., Darienzo, C. J.,
Custer, L. L., Price, J. L., Johnson, J. M., Biller, S. A., Zahler, R. and
Ostrowski, J. (2007) Tandem optimization of target activity and elimination
of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based
selective androgen receptor modulators Bioorg Med Chem Lett 17, 1860-4.
Hanada, K., Furuya, K., Yamamoto, N., Nejishima, H., Ichikawa, K.,
Nakamura, T., Miyakawa, M., Amano, S., Sumita, Y. and Oguro, N. (2003)
Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen
receptor modulator (SARM), in rat models of osteoporosis Biol Pharm
Bull 26, 1563-9.
Hanada, K., Furuya, K., Inoguchi, K., Miyakawa, M. and Nagata, N. (2001)
Tetrahydroquinoline derivatives WO2001 027086.
Hanney, B., Kim, Y., Krout, M. R., Meissner, R. S., Mitchell, H. J.,
Musselman, J., Perkins, J. J. and Wang, J. (2005)
N-(2-Benzyl)-2-phenylbutanamides as androgen receptor modulators
US2005 277681.
Heery, D. M., Kalkhoven, E., Hoare, S. and Parker, M. G. (1997) A
signature motif in transcriptional co-activators mediates binding to nuclear
receptors Nature 387, 733-6.
Heinlein, C. A. and Chang, C. (2002) Androgen receptor (AR) coregulators:
an overview Endocr Rev 23, 175-200.
He, Y., Yin, D., Perera, M., Kirkovsky, L., Stourman, N., Li, W., Dalton,
J.T. and Miller, D. D. (2002a) Novel nonsteroidal ligands with high binding
affinity and potent functional activity for the androgen receptor Eur J Med
Chem 37, 619-34.
Hershberger, L. G., Shipley, E. G. and Meyer, R. K. (1953) Myotrophic
activity of 19-nortestosterone and other steroids determined by modified
levator ani muscle method Proc Soc Exp Biol Med 83, 175-80.
He, B., Minges, J.T., Lee, L.W. and Wilson, E. M. (2002b) The FXXLF
motif mediates androgen receptor-specific interactions with coregulators
J Biol Chem 277, 10226-35.
Higuchi, R. I., Edwards, J. P., Caferro, T. R., Ringgenberg, J. D., Kong,
J.W., Hamann, L. G., Arienti, K. L., Marschke, K. B., Davis, R. L., Farmer,
L. J. and Jones, T. K. (1999) 4-Alkyl- and
3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinolines: potent,
nonsteroidal androgen receptor agonists Bioorg Med Chem Lett 9,
1335-40.
Higuchi, R., Arienti, K. L., Neelakandha, M., Pio, B., Zhi, L., Chen, P. and
Caferro, T. R. (2002) Androgen receptor modulator compounds and
methods US 6,462,038.
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06010 | Page 22 of 26
Review SARMs in development
Higuchi, R. I., Arienti, K. L., Lopez, F. J., Mani, N. S., Mais, D. E., Caferro,
T. R., Long, Y. O., Jones, T. K., Edwards, J. P., Zhi, L., Schrader, W.T.,
Negro-Vilar, A. and Marschke, K. B. (2007b) Novel series of potent,
nonsteroidal, selective androgen receptor modulators based on
7H-[1,4]oxazino[3,2-g]quinolin-7-ones J Med Chem 50, 2486-96.
Higuchi, R. I., Thompson, A.W., Chen, J. H., Caferro, T. R., Cummings,
M. L., Deckhut, C. P., Adams, M. E., Tegley, C. M., Edwards, J. P., Lopez,
F. J., Kallel, E. A., Karanewsky, D. S., Schrader, W.T., Marschke, K. B.
and Zhi, L. (2007a) Potent, nonsteroidal selective androgen receptor
modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones
Bioorg Med Chem Lett 17, 5442-6.
Huber, D. M., Bendixen, A. C., Pathrose, P., Srivastava, S., Dienger, K.
M., Shevde, N. K. and Pike, J.W. (2001) Androgens suppress osteoclast
formation induced by RANKL and macrophage-colony stimulating factor
Endocrinology 142, 3800-8.
Inui, A. (2002) Cancer anorexia-cachexia syndrome: current issues in
research and management CA Cancer J Clin 52, 72-91.
Iversen, P., Johansson, J. E., Lodding, P., Lukkarinen, O., Lundmo, P.,
Klarskov, P., Tammela, T. L., Tasdemir, I., Morris, T. and Carroll, K. (2004)
Bicalutamide (150 mg) versus placebo as immediate therapy alone or as
adjuvant to therapy with curative intent for early nonmetastatic prostate
cancer: 5.3-year median followup from the Scandinavian Prostate Cancer
Group Study Number 6 J Urol 172, 1871-6.
Jenster, G., van der Korput, H. A., van Vroonhoven, C., van der Kwast,
T. H., Trapman, J. and Brinkmann, A. O. (1991) Domains of the human
androgen receptor involved in steroid binding, transcriptional activation,
and subcellular localization Mol Endocrinol 5, 1396-404.
Kang, H.Y., Yeh, S., Fujimoto, N. and Chang, C. (1999) Cloning and
characterization of human prostate coactivator ARA54, a novel protein
that associates with the androgen receptor J Biol Chem 274, 8570-6.
Kang, H.Y., Cho, C. L., Huang, K. L., Wang, J. C., Hu, Y. C., Lin, H. K.,
Chang, C. and Huang, K. E. (2004) Nongenomic androgen activation of
phosphatidylinositol 3-kinase/Akt signaling pathway in MC3T3-E1
osteoblasts J Bone Miner Res 19, 1181-90.
Kawano, H. and Kawaguchi, H. (2006) [Androgen function on skeletal
tissues: analysis of androgen receptor-deficient mice] Clin Calcium 16,
455-60.
Kawano, H., Sato, T., Yamada, T., Matsumoto, T., Sekine, K., Watanabe,
T., Nakamura, T., Fukuda, T., Yoshimura, K., Yoshizawa, T., Aihara, K.,
Yamamoto, Y., Nakamichi, Y., Metzger, D., Chambon, P., Nakamura, K.,
Kawaguchi, H. and Kato, S. (2003) Suppressive function of androgen
receptor in bone resorption Proc Natl Acad Sci U S A 100, 9416-21.
Kazmin, D., Prytkova, T., Cook, C. E., Wolfinger, R., Chu, T. M., Beratan,
D., Norris, J. D., Chang, C.Y. and McDonnell, D. P. (2006) Linking
ligand-induced alterations in androgen receptor structure to differential
gene expression: a first step in the rational design of selective androgen
receptor modulators Mol Endocrinol 20, 1201-17.
Kearbey, J. D., Wu, D., Gao, W., Miller, D. D. and Dalton, J.T. (2004)
Pharmacokinetics of
S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-
3-trifluoromethyl-phenyl)-propionamide in rats, a non-steroidal selective
androgen receptor modulator Xenobiotica 34, 273-80.
Kearbey, J. D., Gao, W., Narayanan, R., Fisher, S. J., Wu, D., Miller, D.
D. and Dalton, J.T. (2007) Selective Androgen Receptor Modulator
(SARM) Treatment Prevents Bone Loss and Reduces Body Fat in
Ovariectomized Rats Pharm Res 24, 328-35.
Kim, Y., Spencer, K. L., Hanney, B. and Duggan, M. E. (2004)
Carbonylamino-benzimidazole derivatives as androgen receptor
modulators WO2004 041277.
Kim, Y., Close, J., Duggan, M. E., Hanney, B., Meissner, R. S.,
Musselman, J., Perkins, J. J. and Wang, J. (2006)
N-(pyridin-3-yl)-2-phenylbutanamides as androgen receptor modulators
WO2006 060108.
Kim, J., Wu, D., Hwang, D. J., Miller, D. D. and Dalton, J.T. (2005) The
para substituent of
S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-prop
ionamides is a major structural determinant of in vivo disposition and
activity of selective androgen receptor modulators J Pharmacol Exp Ther
315, 230-9.
Kousteni, S., Bellido, T., Plotkin, L. I., O'Brien, C. A., Bodenner, D. L.,
Han, L., Han, K., DiGregorio, G. B., Katzenellenbogen, J. A.,
Katzenellenbogen, B. S., Roberson, P. K., Weinstein, R. S., Jilka, R. L.
and Manolagas, S. C. (2001) Nongenotropic, sex-nonspecific signaling
through the estrogen or androgen receptors: dissociation from
transcriptional activity Cell 104, 719-30.
Lambert, C. P., Sullivan, D. H., Freeling, S. A., Lindquist, D. M. and Evans,
W. J. (2002) Effects of testosterone replacement and/or resistance
exercise on the composition of megestrol acetate stimulated weight gain
in elderly men: a randomized controlled trial J Clin Endocrinol Metab 87,
2100-6.
Lanter, J. C., Fiordeliso, J. J., Allan, G. F., Musto, A., Hahn do, W. and
Sui, Z. (2006a) A bioisosteric approach to the discovery of indole carbinol
androgen receptor ligands Bioorg Med Chem Lett 16, 5646-9.
Lanter, J. C., Sui, Z., Fiordeliso, J. J., Jiang, W. and Zhang, X. (2005b)
Novel indole derivatives as selective androgen receptor modulators
(SARMs) US2005 250741.
Lanter, J. C., Sui, Z., Fiordeliso, J. J., Jiang, W. and Zhang, X. (2005a)
Novel indole derivatives as selective androgen receptor modulators
(SARMs) US2005 245485.
Lanter, J. C. and Sui, Z. (2006b) Novel imidazolidin-2-one derivatives as
selective androgen receptor modulators (SARMs) US2006 0063819.
Lanter, J. C., Fiordeliso, J. J., Jiang, W., Allan, G. F., Lai, M. T., Linton,
O., Hahn do, W., Lundeen, S. G. and Sui, Z. (2007) The discovery of a
potent orally efficacious indole androgen receptor antagonist through in
vivo screening Bioorg Med Chem Lett 17, 123-6.
Leder, B. (2007) Gonadal steroids and bone metabolism in men Curr
Opin Endocrinol Diabetes Obes 14, 241-6.
Li, J. J., Sutton, J. C., Nirschl, A., Zou, Y., Wang, H., Sun, C., π, Z.,
Johnson, R., Krystek, S. R., Jr., Seethala, R., Golla, R., Sleph, P. G.,
Beehler, B. C., Grover, G. J., Fura, A., Vyas, V. P., Li, C.Y., Gougoutas,
J. Z., Galella, M. A., Zahler, R., Ostrowski, J. and Hamann, L. G. (2007)
Discovery of Potent and Muscle Selective Androgen Receptor Modulators
through Scaffold Modifications J Med Chem 50, 3015-3025.
Likhite, V. S., Stossi, F., Kim, K., Katzenellenbogen, B. S. and
Katzenellenbogen, J. A. (2006) Kinase-specific phosphorylation of the
estrogen receptor changes receptor interactions with ligand,
deoxyribonucleic acid, and coregulators associated with alterations in
estrogen and tamoxifen activity Mol Endocrinol 20, 3120-32.
Link, J.T., Sorensen, B., Patel, J., Grynfarb, M., Goos-Nilsson, A., Wang,
J., Fung, S., Wilcox, D., Zinker, B., Nguyen, P., Hickman, B., Schmidt, J.
M., Swanson, S., Tian, Z., Reisch, T. J., Rotert, G., Du, J., Lane, B., von
Geldern, T.W. and Jacobson, P. B. (2005) Antidiabetic activity of passive
nonsteroidal glucocorticoid receptor modulators J Med Chem 48,
5295-304.
Liu, L., Wang, L., Zhao, Y., Wang, Y., Wang, Z. and Qiao, Z. (2006)
Testosterone attenuates p38 MAPK pathway during Leishmania donovani
infection of macrophages Parasitol Res 99, 189-93.
Lu, N. Z., Wardell, S. E., Burnstein, K. L., Defranco, D., Fuller, P. J.,
Giguere, V., Hochberg, R. B., McKay, L., Renoir, J. M., Weigel, N. L.,
Wilson, E. M., McDonnell, D. P. and Cidlowski, J. A. (2006) International
Union of Pharmacology. LXV.The pharmacology and classification of the
nuclear receptor superfamily: glucocorticoid, mineralocorticoid,
progesterone, and androgen receptors Pharmacol Rev 58, 782-97.
Lutz, L. B., Jamnongjit, M., Yang, W. H., Jahani, D., Gill, A. and Hammes,
S. R. (2003) Selective modulation of genomic and nongenomic androgen
responses by androgen receptor ligands Mol Endocrinol 17, 1106-16.
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06010 | Page 23 of 26
Review SARMs in development
MacLean, H. E., Warne, G. L. and Zajac, J. D. (1997) Localization of
functional domains in the androgen receptor J Steroid Biochem Mol Biol
62, 233-42.
Malcolm, J. B., Derweesh, I. H., Kincade, M. C., DiBlasio, C. J., Lamar,
K. D., Wake, R.W. and Patterson, A. L. (2007) Osteoporosis and fractures
after androgen deprivation initiation for prostate cancer Can J Urol 14,
3551-9.
Manfredi, M. C., Bi, Y., Nirschl, A. A., Sutton, J. C., Seethala, R., Golla,
R., Beehler, B. C., Sleph, P. G., Grover, G. J., Ostrowski, J. and Hamann,
L. G. (2007) Synthesis and SAR of
tetrahydropyrrolo[1,2-b][1,2,5]thiadiazol-2(3H)-one 1,1-dioxide analogues
as highly potent selective androgen receptor modulators Bioorg Med
Chem Lett 17, 4487-90.
Marhefka, C. A., Gao, W., Chung, K., Kim, J., He, Y., Yin, D., Bohl, C.,
Dalton, J.T. and Miller, D. D. (2004) Design, synthesis, and biological
characterization of metabolically stable selective androgen receptor
modulators J Med Chem 47, 993-8.
Marhefka, C. A., Moore, B. M., 2nd, Bishop, T. C., Kirkovsky, L.,
Mukherjee, A., Dalton, J.T. and Miller, D. D. (2001) Homology modeling
using multiple molecular dynamics simulations and docking studies of
the human androgen receptor ligand binding domain bound to testosterone
and nonsteroidal ligands J Med Chem 44, 1729-40.
Martinborough, E., Shen, Y., Oeveren, A., Long, Y. O., Lau, T. L.,
Marschke, K. B., Chang, W.Y., Lopez, F. J., Vajda, E. G., Rix, P. J.,
Viveros, O. H., Negro-Vilar, A. and Zhi, L. (2007) Substituted
6-(1-pyrrolidine)quinolin-2(1H)-ones as novel selective androgen receptor
modulators J Med Chem 50, 5049-52.
Marzetti, E. and Leeuwenburgh, C. (2006) Skeletal muscle apoptosis,
sarcopenia and frailty at old age Exp Gerontol 41, 1234-8.
Matias, P. M., Donner, P., Coelho, R., Thomaz, M., Peixoto, C., Macedo,
S., Otto, N., Joschko, S., Scholz, P., Wegg, A., Basler, S., Schafer, M.,
Egner, U. and Carrondo, M. A. (2000) Structural evidence for ligand
specificity in the binding domain of the human androgen receptor.
Implications for pathogenic gene mutations J Biol Chem 275, 26164-71.
Matzkin, H. and Soloway, M. S. (1992) Immunohistochemical evidence
of the existence and localization of aromatase in human prostatic tissues
Prostate 21, 309-14.
. (2008) Androgen Receptor Gene Mutations Database World Wide Web
Server, http://androgendb.mcgill.ca/map.gif
http://androgendb.mcgill.ca/map.gif
McInerney, E. M., Weis, K. E., Sun, J., Mosselman, S. and
Katzenellenbogen, B. S. (1998) Transcription activation by the human
estrogen receptor subtype β (ER β) studied with ER β and ER α receptor
chimeras Endocrinology 139, 4513-22.
Meissner, R. S. and Mitchell, H. J. (2005) 17-Heterocyclic-4-azasteroid
derivatives as androgen receptor modulators WO2005 0025579.
Meissner, R. S. and Perkins, J. J. (2004) Androgen receptor modulators
and methods of use thereof WO2004 0100874.
Meissner, R. S. and Perkins, J. J. (2006) Androgen receptor modulators
and methods of use thereof US2006 0241107.
Meissner, R. S. and Perkins, J. J. (2003) Fluorinated 4-azasteroid
derivatives as androgen receptor modulators WO2003 077919.
Melstrom, L. G., Melstrom, K. A., Jr., Ding, X. Z. and Adrian, T. E. (2007)
Mechanisms of skeletal muscle degradation and its therapy in cancer
cachexia Histol Histopathol 22, 805-14.
Miner, J. N., Chang, W., Chapman, M. S., Finn, P. D., Hong, M. H., Lopez,
F. J., Marschke, K. B., Rosen, J., Schrader, W., Turner, R., van Oeveren,
A., Viveros, H., Zhi, L. and Negro-Vilar, A. (2007) An orally active selective
androgen receptor modulator is efficacious on bone, muscle, and sex
function with reduced impact on prostate Endocrinology 148, 363-73.
Miyakawa, M., Sumita, Y., Furuya, K., Ichikawa, K., Hanada, K., Amano,
S. and Nejishima, H. (2004c) Androgen receptor agonist WO2004 000816.
Miyakawa, M., Oguro, N., Hanada, K. and Furuya, K. (2004b) Novel
tetrahydroquinoline derivatives WO2004 013104.
Miyakawa, M., Amano, S., Kamei, M., Hanada, K. and Furuya, K. (2004a)
Tetrahydroquinoline compounds 2004 US 6,777,427.
Mohler, M. L., He, Yali, Wu, Z., Hong, S. S. and Miller, D. D. (2007b)
Dissociated Nonsteroidal Glucocorticoids: Tuning Out Untoward Effects
Expert Opinion in Therapeutic Patents 17, 37-58.
Mohler, M. L., Y. He, Z.Wu, S. S. Hong, and D. D. Miller (2007a)
Nonsteroidal Glucocorticoid Receptor Antagonists: The Race to Replace
RU-486 for Anti-Glucocorticoid Effects Expert Opinion in Therapeutic
Patents 17, 59-81.
Mohler, M. L., Nair, V. A., Hwang, D. J., Rakov, I. M., Patil, R. and Miller,
D. D. (2005) Nonsteroidal Tissue Selective Androgen Receptor
Modulators: A Promising Class of Clinical Candidates Expert Opin Ther
Patents 15, 1565-1585.
Wiley-VCHMohler, M. L., He, Y., Hwang, D. J.,, Bohl, C. E., Narayanan,
R., Dalton, J.T. and Miller, D. D. (2008) Nuclear Receptors as Drug
Targets (in press); Chapter 9: Nonsteroidal Tissue Selective Androgen
Receptor Modulators Methods and Principles in Medicinal Chemistry
(Wiley-VCH)
Morley, J. E., Kim, M. J. and Haren, M.T. (2005) Frailty and hormones
Rev Endocr Metab Disord 6, 101-8.
Nantermet, P. V., Masarachia, P., Gentile, M. A., Pennypacker, B., Xu,
J., Holder, D., Gerhold, D., Towler, D., Schmidt, A., Kimmel, D. B.,
Freedman, L. P., Harada, S. and Ray, W. J. (2005) Androgenic induction
of growth and differentiation in the rodent uterus involves the modulation
of estrogen-regulated genetic pathways Endocrinology 146, 564-78.
Negro-Vilar, A. (1999) Selective androgen receptor modulators (SARMs):
a novel approach to androgen therapy for the new millennium J Clin
Endocrinol Metab 84, 3459-62.
Ng, R. A., Guan, J., Alford, V. C., Jr., Lanter, J. C., Allan, G. F., Sbriscia,
T., Lundeen, S. G. and Sui, Z. (2007b)
2-(2,2,2-Trifluoroethyl)-5,6-dichlorobenzimidazole derivatives as potent
androgen receptor antagonists Bioorg Med Chem Lett 17, 955-8.
Ng, R. A. and Sui, Z. (2004) Thiazoline derivatives as selective androgen
receptor modulators (SARMs) WO2004 113309.
Ng, R. A., Guan, J., Alford, V. C., Jr., Lanter, J. C., Allan, G. F., Sbriscia,
T., Linton, O., Lundeen, S. G. and Sui, Z. (2007a) Synthesis and SAR of
potent and selective androgen receptor antagonists:
5,6-Dichloro-benzimidazole derivatives Bioorg Med Chem Lett 17, 784-8.
Ng, R. A., Lanter, J. C., Alford, V. C., Allan, G. F., Sbriscia, T., Lundeen,
S. G. and Sui, Z. (2007c) Synthesis of potent and tissue-selective
androgen receptor modulators (SARMs):
2-(2,2,2)-Trifluoroethyl-benzimidazole scaffold Bioorg Med Chem Lett 17,
1784-7.
. (2008) NIH, ClinicalTrials.gov (A service of the U.S. National Institutes
of Health), http://www.clinicaltrials.gov http://www.clinicaltrials.gov
Ostrowski, J., Kuhns, J. E., Lupisella, J. A., Manfredi, M. C., Beehler, B.
C., Krystek, S. R., Jr., Bi, Y., Sun, C., Seethala, R., Golla, R., Sleph, P.
G., Fura, A., An, Y., Kish, K. F., Sack, J. S., Mookhtiar, K. A., Grover, G.
J. and Hamann, L. G. (2007) Pharmacological and x-ray structural
characterization of a novel selective androgen receptor modulator: potent
hyperanabolic stimulation of skeletal muscle with hypostimulation of
prostate in rats Endocrinology 148, 4-12.
Owen, G. I. and Zelent, A. (2000) Origins and evolutionary diversification
of the nuclear receptor superfamily Cell Mol Life Sci 57, 809-27.
Pajonk, F., van Ophoven, A. and McBride, W. H. (2005)
Hyperthermia-induced proteasome inhibition and loss of androgen receptor
expression in human prostate cancer cells Cancer Res 65, 4836-43.
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06010 | Page 24 of 26
Review SARMs in development
Palazzolo, I., Burnett, B. G., Young, J. E., Brenne, P. L., La Spada, A.
R., Fischbeck, K. H., Howell, B.W. and Pennuto, M. (2007) Akt blocks
ligand binding and protects against expanded polyglutamine androgen
receptor toxicity Hum Mol Genet 16, 1593-603.
Palazzolo, I., Gliozzi, A., Rusmini, P., Sau, D., Crippa, V., Simonini, F.,
Onesto, E., Bolzoni, E. and Poletti, A. (2008) The role of the polyglutamine
tract in androgen receptor J Steroid Biochem Mol Biol 108, 245-53.
Palesty, J. A. and Dudrick, S. J. (2003) What we have learned about
cachexia in gastrointestinal cancer Dig Dis 21, 198-213.
Perkins, J. J., McVean, C. A., Hanney, B., Meissner, R. S. and Kim, Y.
(2007) N-(Pyridin-4-yl)-2-phenylbutanamides as androgen receptor
modulators WO2007 016358.
Perlmutter, M. A. and Lepor, H. (2007) Androgen deprivation therapy in
the treatment of advanced prostate cancer Rev Urol 9 Suppl 1, S3-8.
Rosen, J. and Negro-Vilar, A. (2002) Novel, non-steroidal, selective
androgen receptor modulators (SARMs) with anabolic activity in bone
and muscle and improved safety profile J Musculoskelet Neuronal Interact
2, 222-4.
Sack, J. S., Kish, K. F., Wang, C., Attar, R. M., Kiefer, S. E., An, Y., Wu,
G.Y., Scheffler, J. E., Salvati, M. E., Krystek, S. R., Jr., Weinmann, R.
and Einspahr, H. M. (2001) Crystallographic structures of the
ligand-binding domains of the androgen receptor and its T877A mutant
complexed with the natural agonist dihydrotestosterone Proc Natl Acad
Sci U S A 98, 4904-9.
Salvati, M. E., Balog, A., Wei, D. D., Pickering, D., Attar, R. M., Geng, J.,
Rizzo, C. A., Hunt, J.T., Gottardis, M. M., Weinmann, R. and Martinez,
R. (2005b) Identification of a novel class of androgen receptor antagonists
based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus Bioorg Med
Chem Lett 15, 389-93.
Salvati, M. E., Balog, A., Shan, W., Wei, D. D., Pickering, D., Attar, R.
M., Geng, J., Rizzo, C. A., Gottardis, M. M., Weinmann, R., Krystek, S.
R., Sack, J., An, Y. and Kish, K. (2005a) Structure based approach to the
design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor
antagonists Bioorg Med Chem Lett 15, 271-6.
Schlienger, N., Thygesen, M. B., Pawlas, J., Badalassi, F., Lewinsky, R.
H., Lund, B.W. and Olsson, R. (2006) Aminophenyl derivatives as
selective androgen receptor modulators US2006 0160845.
Schlienger, N., Pawlas, J., Fejzic, A., Olsson, R., Lund, B.W., Badalassi,
F., Lewinsky, R. and Thygesen, M. B. (2005) Androgen receptor
modulators and method of treating disease using the same WO2005
115361.
Shaffer, P. L., Jivan, A., Dollins, D. E., Claessens, F. and Gewirth, D.T.
(2004) Structural basis of androgen receptor binding to selective androgen
response elements Proc Natl Acad Sci U S A 101, 4758-63.
Shang, Y., Hu, X., DiRenzo, J., Lazar, M. A. and Brown, M. (2000)
Cofactor dynamics and sufficiency in estrogen receptor-regulated
transcription Cell 103, 843-52.
Shang, Y., Myers, M. and Brown, M. (2002) Formation of the androgen
receptor transcription complex Mol Cell 9, 601-10.
Shiau, A. K., Barstad, D., Loria, P. M., Cheng, L., Kushner, P. J., Agard,
D. A. and Greene, G. L. (1998) The structural basis of estrogen
receptor/coactivator recognition and the antagonism of this interaction by
tamoxifen Cell 95, 927-37.
Simental, J. A., Sar, M., Lane, M.V., French, F. S. and Wilson, E. M.
(1991) Transcriptional activation and nuclear targeting signals of the
human androgen receptor J Biol Chem 266, 510-8.
Smith, C. L. and O'Malley, B. W. (2004) Coregulator function: a key to
understanding tissue specificity of selective receptor modulators Endocr
Rev 25, 45-71.
Soderholm, A. A., Lehtovuori, P. T. and Nyronen, T. H. (2005)
Three-dimensional structure-activity relationships of nonsteroidal ligands
in complex with androgen receptor ligand-binding domain J Med Chem
48, 917-25.
Song, E. K., Yeom, J. H., Shin, H.T., Kim, S. H., Shin, W. G. and Oh, J.
M. (2006) Effectiveness of raloxifene on bone mineral density and serum
lipid levels in post-menopausal women with low BMD after discontinuation
of hormone replacement therapy J Clin Pharm Ther 31, 421-7.
Sun, C., Robl, J. A., Wang, T. C., Huang, Y., Kuhns, J. E., Lupisella, J.
A., Beehler, B. C., Golla, R., Sleph, P. G., Seethala, R., Fura, A., Krystek,
S. R., Jr., An, Y., Malley, M. F., Sack, J. S., Salvati, M. E., Grover, G. J.,
Ostrowski, J. and Hamann, L. G. (2006) Discovery of potent, orally-active,
and muscle-selective androgen receptor modulators based on an
N-aryl-hydroxybicyclohydantoin scaffold J Med Chem 49, 7596-9.
Tabata, Y., Iizuka, Y., Shinei, R., Kurihara, K., Okonogi, T., Hoshiko, S.
and Kurata, Y. (2003) CP8668, a novel orally active nonsteroidal
progesterone receptor modulator with tetrahydrobenzindolone skeleton
Eur J Pharmacol 461, 73-8.
Tanenbaum, D. M., Wang, Y., Williams, S. P. and Sigler, P. B. (1998)
Crystallographic comparison of the estrogen and progesterone receptor's
ligand binding domains Proc Natl Acad Sci U S A 95, 5998-6003.
Tilley, W. D., Buchanan, G., Hickey, T. E. and Bentel, J. M. (1996)
Mutations in the androgen receptor gene are associated with progression
of human prostate cancer to androgen independence Clin Cancer Res
2, 277-85.
Trump, R. P., Blanc, J. B., Stewart, E. L., Brown, P. J., Caivano, M., Gray,
D.W., Hoekstra, W. J., Willson, T. M., Han, B. and Turnbull, P. (2007)
Design and synthesis of an array of selective androgen receptor
modulators J Comb Chem 9, 107-14.
Tsai, M. J. and O'Malley, B. W. (1994) Molecular mechanisms of action
of steroid/thyroid receptor superfamily members Annu Rev Biochem 63,
451-86.
Tsugaya, M., Harada, N., Tozawa, K., Yamada, Y., Hayashi, Y., Tanaka,
S., Maruyama, K. and Kohri, K. (1996) Aromatase mRNA levels in benign
prostatic hyperplasia and prostate cancer Int J Urol 3, 292-6.
Turnbull, P. S., Cadilla, R., Larkin, A. L., Stewart, E. L. and Stetson, K.
(2006) Chemical compounds WO2006 133216.
Turnbull, P. S., Cadilla, R., Cowan, D. J., Larkin, A. L., Kaldor, I. and
Stewart, E. L. (2005) Aniline derivatives as selective androgen receptor
modulators WO2005 085185.
Turnbull, P. S., Larkin, A. L., Kaldor, I., Cadilla, R., Cowan, D. J. and
Stewart, E. L. (2006) Chemical compounds WO2006 044707.
van de Wijngaart, D. J., van Royen, M. E., Hersmus, R., Pike, A. C.,
Houtsmuller, A. B., Jenster, G., Trapman, J. and Dubbink, H. J. (2006)
Novel FXXFF and FXXMF motifs in androgen receptor cofactors mediate
high affinity and specific interactions with the ligand-binding domain J Biol
Chem 281, 19407-16.
van Oeveren, A., Motamedi, M., Mani, N. S., Marschke, K. B., Lopez, F.
J., Schrader, W.T., Negro-Vilar, A. and Zhi, L. (2006) Discovery of
6-N,N-bis(2,2,2-trifluoroethyl)amino-4-trifluoromethylquinolin-2(1H)-one
as a novel selective androgen receptor modulator J Med Chem 49, 6143-6.
van Oeveren, A., Pio, B. A., Tegley, C. M., Higuchi, R. I., Wu, M., Jones,
T. K., Marschke, K. B., Negro-Vilar, A. and Zhi, L. (2007b) Discovery of
an androgen receptor modulator pharmacophore based on 2-quinolinones
Bioorg Med Chem Lett 17, 1523-6.
van Oeveren, A., Motamedi, M., Martinborough, E., Zhao, S., Shen, Y.,
West, S., Chang, W., Kallel, A., Marschke, K. B., Lopez, F. J., Negro-Vilar,
A. and Zhi, L. (2007a) Novel selective androgen receptor modulators:
SAR studies on 6-bisalkylamino-2-quinolinones Bioorg Med Chem Lett
17, 1527-31.
Verrijdt, G., Haelens, A. and Claessens, F. (2003) Selective DNA
recognition by the androgen receptor as a mechanism for hormone-specific
regulation of gene expression Mol Genet Metab 78, 175-85.
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06010 | Page 25 of 26
Review SARMs in development
Volicer, L., Stelly, M., Morris, J., McLaughlin, J. and Volicer, B. J. (1997)
Effects of dronabinol on anorexia and disturbed behavior in patients with
Alzheimer's disease Int J Geriatr Psychiatry 12, 913-9.
Wang, C. and Uchida, T. (1997) [Androgen receptor gene mutations in
prostate cancer] Nippon Hinyokika Gakkai Zasshi 88, 550-6.
Wang, J. and McVean, C. A. (2005) 17-β-4-acetamide-4-azasteroids as
androgen receptor modulators WO2005 099707.
Wang, J. and Close, J. (2006b) Androgen receptor modulators WO2006
0026196.
Wang, J. (2004) Androstanes as androgen receptor modulators US2004
0235808.
Wang, Q., Carroll, J. S. and Brown, M. (2005) Spatial and temporal
recruitment of androgen receptor and its coactivators involves
chromosomal looping and polymerase tracking Mol Cell 19, 631-42.
Wang, F., Liu, X. Q., Li, H., Liang, K. N., Miner, J. N., Hong, M., Kallel,
E. A., van Oeveren, A., Zhi, L. and Jiang, T. (2006a) Structure of the
ligand-binding domain (LBD) of human androgen receptor in complex
with a selective modulator LGD2226 Acta Crystallograph Sect F Struct
Biol Cryst Commun 62, 1067-71.
Ward, H.W. (1973) Anti-oestrogen therapy for breast cancer: a trial of
tamoxifen at two dose levels Br Med J 1, 13-4.
Wilson, C. M. and McPhaul, M. J. (1996) A and B forms of the androgen
receptor are expressed in a variety of human tissues Mol Cell Endocrinol
120, 51-7.
Wilson, C. M. and McPhaul, M. J. (1994) A and B forms of the androgen
receptor are present in human genital skin fibroblasts Proc Natl Acad Sci
U S A 91, 1234-8.
Wilson, E. M. (2007) Muscle-bound? A tissue-selective nonsteroidal
androgen receptor modulator Endocrinology 148, 1-3.
Windsor, J. A. and Hill, G. L. (1988) Weight loss with physiologic
impairment. A basic indicator of surgical risk Ann Surg 207, 290-6.
Wirth, M. P., See, W. A., McLeod, D. G., Iversen, P., Morris, T. and Carroll,
K. (2004) Bicalutamide 150 mg in addition to standard care in patients
with localized or locally advanced prostate cancer: results from the second
analysis of the early prostate cancer program at median followup of 5.4
years J Urol 172, 1865-70.
Wright, A. S., Douglas, R. C., Thomas, L. N., Lazier, C. B. and Rittmaster,
R. S. (1999) Androgen-induced regrowth in the castrated rat ventral
prostate: role of 5alpha-reductase Endocrinology 140, 4509-15.
Yeh, S. S. and Schuster, M.W. (2006) Megestrol acetate in cachexia and
anorexia Int J Nanomedicine 1, 411-6.
Yeh, S. S., Lovitt, S. and Schuster, M.W. (2007) Pharmacological
treatment of geriatric cachexia: evidence and safety in perspective J Am
Med Dir Assoc 8, 363-77.
Yin, D., He, Y., Perera, M. A., Hong, S. S., Marhefka, C., Stourman, N.,
Kirkovsky, L., Miller, D. D. and Dalton, J.T. (2003a) Key structural features
of nonsteroidal ligands for binding and activation of the androgen receptor
Mol Pharmacol 63, 211-23.
Yin, D., Gao, W., Kearbey, J. D., Xu, H., Chung, K., He, Y., Marhefka, C.
A., Veverka, K. A., Miller, D. D. and Dalton, J.T. (2003c)
Pharmacodynamics of selective androgen receptor modulators J
Pharmacol Exp Ther 304, 1334-40.
Yin, D., Xu, H., He, Y., Kirkovsky, L. I., Miller, D. D. and Dalton, J.T.
(2003b) Pharmacology, pharmacokinetics, and metabolism of
acetothiolutamide, a novel nonsteroidal agonist for the androgen receptor
J Pharmacol Exp Ther 304, 1323-33.
Ylikomi, T., Bocquel, M. T., Berry, M., Gronemeyer, H. and Chambon, P.
(1992) Cooperation of proto-signals for nuclear accumulation of estrogen
and progesterone receptors Embo J 11, 3681-94.
Zhang, X., Li, X., Allan, G. F., Sbriscia, T., Linton, O., Lundeen, S. G. and
Sui, Z. (2007b) Design, synthesis, and in vivo SAR of a novel series of
pyrazolines as potent selective androgen receptor modulators J Med
Chem 50, 3857-69.
Zhang, X., Li, X. and Sui, Z. (2006b) Novel heterocyclic derivatives useful
as SARMs US2006 0211756.
Zhang, X., Li, X., Allan, G. F., Sbriscia, T., Linton, O., Lundeen, S. G. and
Sui, Z. (2007a) Serendipitous discovery of novel imidazolopyrazole
scaffold as selective androgen receptor modulators Bioorg Med Chem
Lett 17, 439-43.
Zhang, X., Allan, G. F., Sbriscia, T., Linton, O., Lundeen, S. G. and Sui,
Z. (2006a) Synthesis and SAR of novel hydantoin derivatives as selective
androgen receptor modulators Bioorg Med Chem Lett 16, 5763-6.
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06010 | Page 26 of 26
Review SARMs in development