Selective androgen receptor modulator
Encyclopedia
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 steroid
s 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.
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. Oral androgens are not currently used due to concerns about liver toxicity.
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.
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.
), increased LDL/HDL
ratios, liver dysfunction, and so forth.
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
.) They are intended to have the same kind of effects as androgenic drugs like anabolic steroid
Anabolic steroid
Anabolic steroids, technically known as anabolic-androgen steroids or colloquially simply as "steroids", are drugs that mimic the effects of testosterone and dihydrotestosterone in the body. They increase protein synthesis within cells, which results in the buildup of cellular tissue ,...
s 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 therapyAndrogen replacement therapy
Androgen replacement therapy is a hormone treatment often prescribed to counter the effects of male Hypogonadism. It is also prescribed to lessen the effects or delay the onset of normal male aging...
are typically injectable or skin delivery formulations of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
or testosterone esters. Injectable forms of testosterone esters (such as testosterone enanthate, propionate
Propionate
The propanoate or propionate ion is C2H5COO− .A propanoic or propionic compound is a salt or ester of propanoic acid....
, 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. Oral androgens are not currently used due to concerns about liver toxicity.
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 osteopeniaOsteopenia
Osteopenia is a condition where bone mineral density is lower than normal. It is considered by many doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis...
or osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, but with no overt signs of hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
, 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 (virilizationVirilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
), increased LDL/HDL
High density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
ratios, liver dysfunction, and so forth.
In clinical testing
- OstarineOstarineOstarine is an investigational selective androgen receptor modulator from GTX, Inc for treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merck & Company.-Structure:According to a recent...
(MK-2866, GTx-024) - affects both muscle and bone, intended mainly for osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
but also general treatment for andropause and reversing muscle sarcopenia in the elderly and for cachexiaCachexiaCachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
in cancer patients. - BMS-564,929BMS-564,929BMS-564,929 is an investigational selective androgen receptor modulator, which is being developed by Bristol-Myers Squibb for treatment of the symptoms of age-related decline in androgen levels in men . These symptoms may include depression, loss of muscle mass and strength, reduction in libido and...
- mainly affects muscle growth, intended as general treatment for symptoms of andropauseAndropauseAndropause or male menopause, sometimes colloquially called "man-opause" is a name that has been given to a menopause-like condition in aging men... - LGD-4033 - pharmacological profile similar to that of OstarineOstarineOstarine is an investigational selective androgen receptor modulator from GTX, Inc for treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merck & Company.-Structure:According to a recent...
Pre-clinical
- AC-262,356AC-262,356AC-262,356 is a drug developed by Acadia Pharmaceuticals which acts as a selective androgen receptor modulator. It acts as a partial agonist for the androgen receptor with a Ki of 5nM, and no significant affinity for any other receptors tested...
- JNJ-28330835.
- LGD-2226LGD-2226LGD-2226 is an investigational selective androgen receptor modulator, which is being developed for treatment of muscle wasting and osteoporosis....
- affects both muscle and bone
- LGD-3303LGD-3303LGD-3303 is a drug which acts as a selective androgen receptor modulator, with good oral bioavailability. It is a selective agonist for the androgen receptor, producing functional selectivity with effective dissociation of anabolic and androgenic effects, acting as a partial agonist for androgenic...
- S-40503S-40503S-40503 is an investigational selective androgen receptor modulator developed by the Japanese company Kaken Pharmaceuticals, which was developed for the treatment of osteoporosis...
- selective for bone tissue, particularly low virilization, intended for osteoporosis and may be suitable for use in women
- S-23S-23 (drug)S-23 is an investigational selective androgen receptor modulator developed by GTX, Inc as a potential male hormonal contraceptive. It binds to the androgen receptor more strongly than older drugs such as andarine with a Ki of 1.7nM, and in animal studies it showed both a good ratio of anabolic to...
- under development as a male hormonal contraceptive
Examples no longer being developed
- AndarineAndarineAndarine is an investigational selective androgen receptor modulator developed by GTX, Inc for treatment of conditions such as muscle wasting, osteoporosis and benign prostatic hypertrophy, using the non-steroidal androgen antagonist bicalutamide as a lead compound.Andarine is an orally active...
("S-4") - partial agonist, intended mainly for treatment of benign prostatic hypertrophy
See also
- Selective receptor modulatorSelective receptor modulatorIn the field of pharmacology, a selective receptor modulator or SRM is a type of drug that has different effects in different tissues. A SRM may behave as an agonist in some tissues while as an antagonist in others. Hence selective receptor modulators are sometimes referred to as tissue selective...
- Selective estrogen receptor modulatorSelective estrogen receptor modulatorSelective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
- Selective progesterone receptor modulatorSelective progesterone receptor modulatorA selective progesterone receptor modulator is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists and full antagonists is that their action differs in different tissues...
- Selective glucocorticoid receptor agonistSelective glucocorticoid receptor agonistA selective glucocorticoid receptor agonist , sometimes called a dissociated glucocorticoid receptor agonist , is a type of experimental drug that is designed to share many of the desirable anti-inflammatory and immunosuppressive properties of classical glucocorticoid drugs but with fewer side...