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
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  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