Selective androgen receptor modulator
Selective androgen receptor modulators or SARMs are a novel class of androgen receptor ligands. (The name follows the terminology currently used for similar molecules targeting the estrogen receptor, "selective estrogen receptor modulators," such as tamoxifen.) They are intended to have the same kind of effects as androgenic drugs like anabolic steroids but be much more selective in their action, allowing them to be used for many more clinical indications than the relatively limited legitimate uses that anabolic steroids are currently approved for.
Comparison to testosterone
Currently used androgens for male hormone replacement therapy are typically injectable or skin delivery formulations of testosterone or testosterone esters. Injectable forms of testosterone esters (such as testosterone enanthate, propionate, or cypionate) produce undesirable fluctuations in testosterone blood levels, with overly high levels shortly after injection and overly low afterward. Skin patches do provide a better blood level profile of testosterone, but skin irritation and daily application still limit their usefulness.
SARMs provide the opportunity to design molecules that can be delivered orally, but that selectively target the androgen receptors in different tissues differently. The goal of research in this area is to allow a customized response: Tissues that are the target of the therapy will respond as they would to testosterone; other tissues where undesirable side-effects are produced will not.
None of the SARMs yet developed are truly selective for anabolic effects in muscle or bone tissues without producing any androgenic effects in tissues such as the prostate gland, however several non-steroidal androgens show a ratio of anabolic to androgenic effects of greater than 3:1 and up to as much as 10:1, compared to testosterone, which has a ratio of 1:1.
This suggests that, while SARMs are likely to show some virilizing effects when used at high doses (e.g., use by bodybuilders), at lower therapeutic doses they may well be effectively selective for anabolic effects, which will be important if SARMs are to have clinical application in the treatment of osteoporosis in women. One substantial advantage of even the first-generation SARMs developed to date is that they are all orally active without causing liver damage, whereas most anabolic steroids are not active orally and must be injected, and those anabolic steroids that are orally active tend to cause dose-dependent liver damage, which can become life-threatening with excessive use. Research is continuing into more potent and selective SARMs, as well as optimising characteristics such as oral bioavailability and increased half-life in vivo, and seeing as the first tissue-selective SARMs were only demonstrated in 2003, the compounds tested so far represent only the first generation of SARMs and future development may produce more selective agents compared to those available at present.
Selectivity in men
For example, if the target is bone growth in elderly men with osteopenia or osteoporosis, but with no overt signs of hypogonadism, a SARM targeting bone and muscle tissue but with lesser activity on the prostate or testes would be more desirable.
Selectivity in women
A SARM for women would ideally stimulate bone retention, or libido and other sexual function that androgens can influence, without negative side-effects such as development of male gender characteristics (virilization), increased LDL/HDL ratios, liver dysfunction, and so forth.
In clinical testing
- Enobosarm (Ostarine, MK-2866, GTx-024) – affects both muscle and bone, intended mainly for osteoporosis but also general treatment for andropause and reversing muscle sarcopenia in the elderly and for cachexia in cancer patients.
- BMS-564,929 – mainly affects muscle growth, intended as general treatment for symptoms of andropause
- LGD-4033 – (Ligandrol) pharmacological profile similar to that of enobosarm.
- LGD-2226 – affects both muscle and bone
- S-40503 – selective for bone tissue, particularly low virilization, intended for osteoporosis and may be suitable for use in women
- S-23 – under development as a male hormonal contraceptive
- According to a recent patent, SARM was made by combining the 4-azasteroid found in 5AR inhibitors (finasteride/dutasteride) with the 17α-methyl-17β-hydroxy pharmacophore ubiquitous among mostly all of the orally active AAS.
Examples no longer being developed
- Acetothiolutamide – high-affinity AR full agonist in vitro, but very low activity in vivo due to poor pharmacokinetics
- Andarine ("S-4") – partial agonist, intended mainly for treatment of benign prostatic hypertrophy
In 2013, some supplement companies began selling various SARMs as supplements, in purported violation of both the Food and Drug Administration's Dietary Supplement Health and Education Act of 1994 (DSHEA) and the intellectual property rights of the patent holders of the compounds.
The controversy reached mainstream media when the quarterback of the Florida Gators, Will Grier, allegedly tested positive for LGD-4033, a claim that the University of Florida denies. The news increased online sales of the compound.
- Selective receptor modulator
- Selective estrogen receptor modulator
- Selective progesterone receptor modulator
- Selective glucocorticoid receptor agonist
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