Selective Androgen Receptor Modulators (SARMs)

Discussion in 'Men's Health Forum' started by Michael Scally MD, Jun 19, 2017.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Development of Selective Androgen Receptor Modulators (SARMs)

    · Review of the status of SARM development.
    · Molecular mechanisms of tissue selectivity.

    The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens.

    However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects.

    In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis.

    This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.

    Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol.

    Attached Files:

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  2. Redrum42

    Redrum42 Member

    ^^ you say they are "tissue selective", this is true? There are few posters I would trust more than you, but I have seen a couple things that suggest otherwise. (E.g. only target skeletal muscle AR?)

    Maybe I just don't understand the meaning/context of "selective" as well as I think I do.
  3. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Amelioration of Sexual Behavior and Motor Activity Deficits in A Castrated Rodent Model with A Selective Androgen Receptor Modulator SARM-2f

    Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models.

    In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity.

    First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues.

    The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone.

    Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities.

    These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia.

    Morimoto M, Amano Y, Oka M, et al. Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f. PLoS One 2017;12:e0189480. Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f
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  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Krishnan V, Patel NJ, Mackrell JG, et al. Development of a selective androgen receptor modulator for transdermal use in hypogonadal patients. Andrology.

    We have identified a non-steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver.

    Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions.

    This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate. When LY305 was tested in animal models of skeletal atrophy it restored the skeletal muscle mass through accelerated repair. In a bone fracture model, LY305 remained osteoprotective in the regenerating tissue and void of deleterious effects.

    Finally, in a small cohort of healthy volunteers, we assessed the safety and tolerability of LY305 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 to hematocrit or HDL after 4-week treatment period.

    Collectively, LY305 represents a first of its kind de novo development of a non-steroidal transdermal SARM with unique properties which could find clinical utility in hypogonadal men.
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  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Bioassay-Based Characterization Of Novel Androgens
    Bioassay-based characterization of novel androgens | ECE2018

    Chemical-analytical methods are currently in use as the gold standard approach for the detection of androgens, designer androgens and selective androgen receptor modulators (SARMs) in serum and urine samples from athletes as well as in sports supplements. These methods are exquisitely sensitive and selective.

    However, they have the disadvantage in that the androgens that being surveyed for must have delineated structures. Designer androgens or SARMs that have divergent structures from the characterized reference list can be missed with analyte methods because their specific analytical fingerprints are not defined.

    In vitro cell based androgen receptor (AR) bioassays are based on probing the biological pathway of androgen action and therefore are capable of identifying the presence of any AR-activating compound in a sample. Moreover, by basing the AR bioassays in different host cells (eg. yeast- no metabolism or cofactors; HEK293- limited metabolism but has cofactors; HuH7- active metabolism and cofactors) the relative AR potency of activating compounds can be measured. Using this tandem AR bioassay approach, 15 SARMs, recently detected as sports doping agents, were analyzed for relative AR potency.

    For S-1, S-6, S-23, S-24, ostarine, andarine, LG-121071, Rad-140, LGD-2226, 93746 and BMS-564929 all showed only moderate intrinsic AR bioactivity in the yeast bioassay, however potency increased dramatically with active metabolism.

    Some of these SARMs showed AR potencies far beyond that measured for the endogenous androgens, testosterone or dihydrotestosterone. AC262536 and MK0773 were weak SARMs even after active metabolism. By contrast, ACP-105 and YK-11 were both potent SARMs, with and without metabolism.

    Together, these results have implications for the anabolic potential of these SARMs, thus they pose a real threat to sports doping.
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    GSK2881078, a SARM, Produces Dose-Dependent Increases in Lean Mass in Healthy Older Men and Women

    GSK2881078 is a non-steroidal, selective androgen receptor modulator (SARM) under investigation by GlaxoSmithKline (GSK) for treatment of reduced mobility and other functional limitation in men and women with muscle weakness associated with chronic and acute illnesses.

    Objective - This was a phase 1b study intended to explore across a dose range the pharmacokinetic (PK) - pharmacodynamic (PD) relationship and further safety and tolerability data for GSK2881078. This study also evaluated effects of CYP3A4 inhibition on pharmacokinetics (PK) of GSK2881078.

    Methods - This was a randomized, placebo controlled, parallel group, repeat dose, dose-escalation study in healthy older males and post-menopausal females. A total of 3 cohorts of males and 3 cohorts of females were studied. Dosing at each dose level was twice daily (BID) for the first 3 days followed by once daily for up to 53 days Repeated dual energy X-Ray absorptiometry (DXA) and magnetic resonance imaging (MRI) cross-sectional thigh scans were performed. The effect of CYP3A4 inhibition on GSK2881078 PK was evaluated in a separate cohort.

    Results - GSK2881078 was generally well tolerated and no serious adverse events (SAEs) were reported. Compared to placebo, there was greater lean mass accrual with all dose levels of GSK2881078. Females exhibited a greater response at lower doses than males. Transient elevations of ALT were observed. The effect of CYP3A4 inhibition on GKS2881078 pharmacokinetics was unlikely to be of clinical significance.

    Conclusions - GSK2881078 yielded dose-dependent increases in lean mass with evidence of enhanced sensitivity in women. The compound was well tolerated.

    D, Clark RV, Magee M, et al. GSK2881078, a SARM, produces dose-dependent increases in lean mass in healthy older men and women. The Journal of Clinical Endocrinology & Metabolism 2018. GSK2881078, a SARM, produces dose-dependent increases in lean mass in healthy older men and women | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Consistent with other SARMs and androgenic steroids, dosing with GSK2881078 produced reversible reductions in levels of testosterone in men. Calculated free testosterone showed a more limited decrease compared with total testosterone due to concurrent decreases in SHBG.

    This was also matched by reductions in sex hormone binding globulin, but not with clinically significant changes in FSH, LH, estradiol, or progesterone. The mechanism of testosterone suppression is not fully understood, particularly in the context of unchanged LH.

    Preclinical studies with GSK2881078 confirmed that the compound crosses the blood/brain barrier, but, unlike testosterone15, it does not appear to influence the hypothalamic-pituitary axis to decrease LH secretion.


    I may be mistaken, but the values for Testosterone appear to be umol/L. I am reading this as micro. From the y-axis, these values are seen as nmol/L [nanomoles].
    Last edited: Jul 3, 2018
  8. Sparkyp

    Sparkyp Member

    Thanks for this Dr. S
    I’m not an educated person on these matters and I’m attempting to comprehend the medical terminology but it appears these studies are showing potential benefits with sarms no?
  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine


    As currently researched, never FDA Approved.
  10. Sparkyp

    Sparkyp Member

    Doesn’t appear it will ever be FDA approved unless large pharma companies are able to patent tested sarms for sale.
  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  12. Kwirion

    Kwirion Member

  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications

    Introduction Selective androgen receptor modulators (SARMs) differentially bind to androgen receptors depending on each SARM’s chemical structure. As a result, SARMs result in anabolic cellular activity while avoiding many of the side effects of currently available anabolic steroids. SARMs have been studied in the treatment of breast cancer and cachexia and have also been used as performance-enhancing agents. Here, we evaluate and summarize the current literature on SARMs.

    Aim To present the background, mechanisms, current and potential clinical applications, as well as risks and benefits of SARMs.

    Methods A literature review was performed in MEDLINE using the terms selective androgen receptor modulator, hypogonadism, cachexia, breast cancer, benign prostatic hyperplasia, libido, and lean muscle mass. Both basic research and clinical studies were included.

    Main Outcome Measure To complete a review of peer-reviewed literature.

    Results Although there are currently no U.S. Food and Drug Agency-approved indications for SARMs, investigators are exploring the potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a paucity of drug interactions. Early clinical studies have demonstrated potential uses for SARMs in the treatment of cancer-related cachexia, benign prostatic hyperplasia (BPH), hypogonadism, and breast cancer, with positive results.

    Conclusion SARMs have numerous possible clinical applications, with promise for the safe use in the treatment of cachexia, BPH, hypogonadism, breast cancer, and prostate cancer.

    Solomon ZJ, Mirabal JR, Mazur DJ, Kohn TP, Lipshultz LI, Pastuszak AW. Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications. Sexual medicine reviews 2018.
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  14. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Selective Androgen Receptor Modulator, S42 Has Anabolic and Anti-Catabolic Effects on Cultured Myotubes

    · A SARM, S42 lowered expression levels of atrogin1 and MuRF1 mRNA in C2C12 myotubes.
    · S42 increased phosphorylation of p70S6K through activation of mTORC1 in C2C12 myotubes.
    · S42 may have anti-catabolic and anabolic effect in vitro.

    We previously identified a novel selective androgen receptor modulator, S42, that does not stimulate prostate growth but has a beneficial effect on lipid metabolism. S42 also increased muscle weight of the levator ani in orchiectomized Sprague–Dawley rats. These findings prompted us to investigate whether S42 has a direct effect on cultured C2C12 myotubes.

    S42 significantly lowered expression levels of the skeletal muscle ubiquitin ligase (muscle atrophy-related gene), atrogin1 and Muscle RING-Finger Protein 1(MuRF1) in C2C12 myotubes, as determined by real time PCR. Phosphorylation of p70 S6 kinase (p70S6K), an essential factor for promoting protein synthesis in skeletal muscle, was significantly increased by S42 to almost the same extent as by insulin, but this was significantly prevented by treatment with rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). However, phosphorylation of Akt, upstream regulator of mTORC1, was not changed by S42. S42 did not increase insulin-like growth factor 1 (Igf1) mRNA levels in C2C12 myotubes.

    These results suggest that S42 may have an anabolic effect through activation of mTORC1–p70S6K signaling, independent of igf-1-Akt signaling and may exert an anti-catabolic effect through inhibition of the degradation pathway in cultured C2C12 myotubes.

    Muta Y, Tanaka T, Hamaguchi Y, et al. Selective androgen receptor modulator, S42 has anabolic and anti-catabolic effects on cultured myotubes. Biochemistry and Biophysics Reports 2019;17:177-81.
  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    QSAR Analysis of a Series of Hydantoin-based Androgen Receptor Modulators and Corresponding Binding Affinities

    Androgen receptor (AR), a member of the nuclear hormone receptor superfamily of intracellular ligand-dependent transcription factors, plays an indispensable role in normal male development through the regulation of androgen through the binding with endogenous androgens. Inappropriate amounts of androgens have a severe adverse effect on men.

    Excessive androgen may contribute to accelerate prostatic hypertrophy, even prostate cancer, while the absence of androgen may result in reduced muscle mass and strength, decreased bone mass, low energy, diminished sexual function and an increased risk of osteoporosis and fracture.

    In these cases, androgen receptor modulators are important to maintain the normal biological function of AR. So androgen receptor modulators are necessary for human being to improve their happy life index.

    To explore the relationships between molecular structures and corresponding binding abilities to aid the new AR modulator design, multiple linear regressions (MLR) are employed to analyze a series of hydantoin analogues, which can bind to androgen receptor acting as AR modulators.

    The obtained optimum model presents wonderful reliabilities and strong predictive abilities with R(2) =0.858, Q L O O 2 =0.822, Q L M O 2 =0.813, Q F 1 2 =0.840, Q F 2 2 =0.807, Q F 3 2 =0.814, CCC=0.893, respectively.

    The derived model can be used to predict the binding abilities of unknown chemicals and may help to design novel molecules with better AR affinity activity.

    Wang X, Han W, Li J. QSAR Analysis of a Series of Hydantoin-based Androgen Receptor Modulators and Corresponding Binding Affinities. Molecular informatics 2019.
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  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Androgen Receptor Modulators: A Review of Recent Patents and Reports (2012-2018)

    INTRODUCTION: Androgen receptor (AR) is one of the most promising targets of drug discovery because of its importance in male reproductive systems and homeostasis of bone and muscle. Various AR-modulating agents have been developed and used clinically to treat androgen-dependent disorders, including prostate cancer, and some new-generation antiandrogens have recently been approved.

    Intensive studies are underway to develop various AR-modulating compounds, including conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional AR-modulating compounds that target sites other than the ligand-binding domain (LBD), such as the N-terminal domain (NTD) or the DNA-binding domain (DBD).

    AREAS COVERED: The authors provide an overview of AR-modulating agents from 2012 to 2018.

    EXPERT OPINION: The LBD has been the primary target for AR modulation, and important AR-modulating agents, including SARMs and recently approved antiandrogens such as enzalutamide and apalutamide, have been developed as conventional LBD antagonists.

    Development of LBD-targeting antiandrogens to treat prostate cancer is a kind of cat-and-mouse game between clinical agents and AR mutations, and therefore next-generation antiandrogens are still required.

    Development of nonconventional AR-modulating agents targeting NTD and DBD, is likely to be a promising approach to develop multiple and synergistic strategies able to overcome any kind of androgen-dependent condition.

    Fujii S, Kagechika H. Androgen receptor modulators: a review of recent patents and reports (2012-2018). Expert opinion on therapeutic patents 2019.
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