Despite evidenced clinical and preclinical studies, no SARM has yet
received full clinical approval. However, the enormous anabolic
properties of SARM muscles and bones give rise to potential misuse in
sports, as has been recognized by the World Anti-Doping Agency (WADA),
which has included SARM in the banned list released annually since 2008
(class S1.2, other anabolic agents) [45].
Due to its considerable variety of central chemical structure and the
display of substantially different physical and chemical properties, the
generation of SARM data related to ionization and dissociation of
substances under analytical conditions commonly used in doping control
laboratories is crucial for routine testing of sports drugs. Therefore,
drug candidates have been subjected to electrospray ionization,
high-resolution mass spectrometry, and electron ionization, to reveal
structural information that supports the development of test methods and
metabolism studies [46].
In this context, LGD-4033 (also known as VK5211, Ligandrol or
Anabolicum) (4 - ((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethy1)
pyrrolidine-1-y1) -2-trifluoro-methyl) benzonitrile) is a SARM with a
central structure of pyrrolidinyl-benzonitrile [47]. A study in
young, healthy men proved that LGD-4033 is safe, well-tolerated, has a
favorable pharmacokinetic profile with a prolonged elimination half-life
(24-36 hours), in addition to showing increased lean body mass. Longer
randomized studies should assess its effectiveness in improving physical
function and health benefits. Although its use is not officially
approved and is not yet manufactured by a pharmaceutical company, many
websites make LGD-4033 widely available and studies have reported its
detection in black market products [47].
A study of LGD-4033 metabolism in human urine, as well as in a doping
control sample from a human athlete, has been reported. The metabolites
of microsomes by the human liver, as well as electrochemical conversion
metabolites / microbial degradation of LGD-4033 have also been described
[47].
GlaxoSmithKline (GSK) 2881078 is a selective non-steroidal SARM
modulator under investigation by GSK for the treatment of reduced
mobility and other functional limitations in men and women with muscle
weakness associated with chronic and acute diseases [48]. Thus, in a
human study, we report the safety, tolerability, pharmacokinetics, and
pharmacodynamics of SARM GSK2881078. In part A, healthy young men (n =
10) received a single dose of the study drug (0 mg, 0.05 mg, 0.1 mg, 0.2
mg gsk2881078 or corresponding placebo). In part b, the cohorts of
repeated doses in men (n = 65) were 0.05 mg, 0.2 mg and 0.08 mg, 0.24
mg, 0.48 mg, 0.75 mg or placebo; in women (n = 24) it was 0.24 mg, 0.35
mg or placebo (7 days for 0.5 mg, 14 days for other doses).
Pharmacokinetic analysis showed dose-proportional increases in exposure
and a long half-life> 100 h. There were no significant
effects on vital signs, electrocardiograms, cardiac telemetry, or
standard clinical laboratory studies. A dose-response effect was
observed in the reduction of high-density lipoprotein and sex
hormone-binding globulin. In women with 0.35 mg, the differences from
placebo were -0.518 (95% confidence interval: -0.703, -0.334) mmol l-1
and -39.1 (-48.5, -29.7 ) nmol l-1, respectively. Women showed greater
sensitivity to these parameters at lower doses than men. Adverse
drug-related events were mild. One woman developed a rash and was
removed. Two men had elevated creatine phosphokinase after physical
exertion during follow-up. Therefore, these data demonstrated
pharmacodynamic effects with acceptable tolerability and support an
additional clinical assessment of this SARM [48].
Still, another phase 1b study aimed at exploring, over a range of doses,
the pharmacokinetic relationship and more safety and tolerability data
for gsk2881078 [49]. This study also evaluated the effects of cyp3a4
inhibition on the pharmacokinetics of gsk2881078. This study followed a
randomized, placebo-controlled, parallel-group, repeated dose, and dose
escalation model in older healthy men and postmenopausal women. Three
male and three female cohorts were studied. Dosing at each dose level
was twice daily for the first 3 days, followed by once daily for up to
53 days. Repeated x-ray absorptiometry and magnetic resonance imaging
were performed in the cross-section of the thigh. The effect of cyp3a4
inhibition on gsk2881078 was evaluated in a separate cohort. The
gsk2881078 was generally well tolerated and no serious adverse events
were reported. Compared with the placebo, there was a greater
accumulation of lean mass with all dose levels of gsk2881078. Women
exhibited a greater response at lower doses than men. Transient
elevations of alanine aminotransferase were observed. The effect of
cyp3a4 inhibition on gks2881078 is likely to have no clinical
significance. Therefore, gsk2881078 produced dose-dependent increases in
lean mass, with evidence of greater sensitivity in women. The compound
was well tolerated [49].
Also, the assembly of inflammasomes after infection or injury leads to
the release of interleukin-1β (IL-1β) and pyroptosis. After activation
of the inflammasome, the pyroptosis cells either enter a hyperactive
state defined by the secretion of IL-1β without cell death. The removal
of the toll-il-1r SARM protein from macrophages decouples the release of
inflammasome-dependent cytokines and pyroptosis, in which cells exhibit
increased production of IL-1β, but reduce pyroptosis in the same way.
The increase in sarm in the cells caused less release of IL-1β and
pyroptosis. SARM suppressed IL-1β by directly restricting the nlrp3
inflammasome and, therefore, caspase-1 activation [50].
A steroid compound was recently detected as (17α, 20e) -17.20 -
[(1-methoxyethylidene) bis (oxy)] - 3-oxo-19-norpregna-4,20-
diene-21-carboxylic acid methyl ester (yk11). This compound is described
as having selective properties of androgen receptor modulators and
myostatin inhibitor. As yk11 is an experimental drug candidate and an
unapproved substance for humans, scientific data on its metabolism is
scarce. Due to its steroid backbone and the undisputably labile derived
orthoester portion, positioned in the d ring, substantial in vivometabolic conversion was anticipated [51].
Also, RA has attracted attention in the treatment of breast cancer. Due
to the undesirable side effects of ar agonists, attempts have been made
to develop selective RA modulators. Thus, one of these compounds is
cl-4as-1. three different breast cancer cell lines were used, namely,
mcf-7 luminal cells, mda-mb-453 apocrine molecular cells, and
triple-negative basal cells, mda-mb-231. The high and significant
agreement was found between dihydrotestosterone (DHT) and cl-4as-1 in
the regulation of gene expression in mda-mb-453 cells. however, some
differences were observed, including the expression of RA, which was
regulated by DHT, but not by cl-4as-1. Also, DHT and cl-4as-1 caused a
similar morphological change and reorganization of the actin structure
of mda-mb-453 cells into a mesenchymal phenotype. Treatment of cells
with dht resulted in the induction of the proliferation of mcf-7 and
mda-mb-453 cells, but no effect was observed on the growth of mda-mb-231
cells. On the other hand, increasing doses of cl-4as-1 resulted in a
dose-dependent inhibition of the growth of the three cell lines. This
inhibition was the result of the induction of apoptosis by which
cl-4as-1 caused a block in the entry of cells in the s phase, followed
by DNA degradation. Therefore, these results indicate that, although
cl-4as-1 has characteristics of the classic RA agonist, it has different
properties that may make it useful in the treatment of breast cancer
[52].
Also, a report described the discovery of RAD140, a potent non-steroidal
selective modulator, orally bioavailable, non-selective steroid for RA.
The characterization of RAD140 in several preclinical models of anabolic
androgen action is also described. RAD140 has excellent pharmacokinetics
and is a potent anabolic also in non-human primates. The general
preclinical profile of RAD140 completed preclinical toxicology in rats
and monkeys. At the moment, RAD140 is being prepared for phase 1
clinical studies in patients suffering from weight loss due to cancer
cachexia [53].
In this sense, loss of muscle mass in cancer is a common and often
hidden condition that can occur before obvious signs of weight loss and
before a clinical diagnosis of cachexia can be made. Muscle wastage in
cancer is an important and independent predictor of progressive
functional impairment, decreased quality of life and increased
mortality. Although several therapeutic agents are currently under
development to treat muscle wasting or cachexia in cancer, most of these
agents do not directly inhibit muscle wasting. Thus, SARMs have the
potential to increase lean body mass and, therefore, muscle mass,
without the undesirable side effects seen with traditional anabolic
agents [54].
Thus, Enobosarm, a non-steroid SARM, is an agent in the clinical
development for preventing and treating muscle wasting in cancer
patients (phase 1 and 2 trials). Also, a phase 3, randomized,
double-blind, placebo-controlled, multicenter, multinational trial was
designed to evaluate the effectiveness of Enobosarm in preventing and
treating muscle wasting in individuals who initiate first-line
chemotherapy for non-chemotherapy. little. In each study, subjects will
receive either placebo (n = 150) or Enobosarm 3 mg (n = 150) orally once
daily for 147 days. Physical function, assessed as the power to climb
stairs, and lean mass assessed by dual-energy x-ray absorptiometry, are
the end points of effectiveness in both tests evaluated on the day.
Based on extensive comments from the Food and Drug Administration (FDA),
an individual should experience a 10% improvement in physical function
compared to the baseline. To meet the definition of response in lean
mass, a subject must have demonstrated no loss of lean mass compared to
the baseline. Secondary end points include the durability of the
assessed response. The efficacy parameters are the result of this
feedback and discussion of the threshold for clinical benefit in
patients at risk of muscle loss. The full results of these studies will
be published shortly [54].
Also, a selective non-steroidal modulator named ly305 has been
identified, which is bioavailable through a transdermal route of
administration while being highly eliminated by hepatic metabolism to
limit the exposure of parent compounds in the liver. The selection of
this compound and its transdermal formulation was based on the
optimization of skin absorption properties using in vitro and in
vivo skin models. This molecule is an agonist of the perineal muscle
and is a weak partial agonist of androgenic tissues, such as the
prostate. When ly305 was tested on animal models of skeletal atrophy, it
restored skeletal muscle mass through accelerated repair. In a model of
bone fracture, ly305 remained osteoprotective in the regenerating tissue
and without deleterious effects. In a small cohort of healthy
volunteers, the safety and tolerability of ly305 was assessed when
administered transdermally. Ly305 showed a dose-dependent increase in
serum exposure and was well tolerated with minimal adverse effects.
Notably, there were no statistically significant changes in hematocrit
or HDL after the 4-week treatment period. Collectively, ly305 represents
the first of its kind to develop a non-steroidal transdermal SARM with
unique properties that may find clinical utility [55].
The gtx-024 (Enobosarm) is the first selective modulator of androgen
receptors of the class, being developed for several indications in
oncology. Pre-clinical studies of gtx-024 supported the evaluation of
several potential drug interactions in a clinical setting. A series of
open phase 1 drug interaction studies was designed to interrogate
possible interactions with a cyp3a4 inhibitor (itraconazole), a cyp3a4
inducer (rifampicin), a pan-ugt inhibitor (probenid), a cyp2c9 substrate
(celecoxib) ) and a bcrp substrate (rosuvastatin). The plasma
pharmacokinetics of gtx-024, its main metabolite (glucuronide gtx-024)
and each substrate were characterized in detail. Administration of
itraconazole did not affect the pharmacokinetics of gtx-024. Likewise,
the administration of gtx-024 did not significantly alter the
pharmacokinetics of celecoxib or rosuvastatin. Administration of
rifampicin had the greatest impact on the pharmacokinetics of gtx-024 of
any co-administered agent and reduced the maximum plasma concentration
by 23% and the area under the curve by 43%. Probenecid had a complex
interaction with gtx-024, so plasma levels of gtx-024 and glucuronide
gtx-024 were increased by coadministration of the ugt inhibitor (50 and
112%, respectively). Overall, gtx-024 was well tolerated and has very
little risk of generating clinically relevant drug interactions
[56].