User:Katievans/Selective androgen receptor modulator

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Selective Androgen Receptor Modulators or SARMs are a novel class of androgen receptor ligands. In the late 1990s researchers were successful in finding the first nonsteroidal SARM, it was the discovery of an analog to bicalutamide; the search for these new drug candidates was driven by the undesirable side effects that come with androgenic-anabolic steroids. They are intended to have the same kind of effects as androgenic drugs but be much more selective in their action, allowing them more uses than those of anabolic steroids. SARMs signify a new era of tissue-selective androgens with an unknown potential to treat (and possibly cure) several diseases.

Comparison to testosterone[edit]

Structure of 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 ability 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 nonsteroidal androgens show a ratio of anabolic to androgenic effects of greater than 3:1 and up to as much as 90:1 (RAD-140), compared to testosterone, which has a ratio of 1:1. Structure of RAD-140 Research is continuing into more potent and selective SARMs, as well as optimizing 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[edit]

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[edit]

A SARM for women  would ideally stimulate bone retention, or libido and other function that androgens can influence, without negative side-effects such as development of male sex characteristics (virilization), increased LDL/HDL ratios, liver dysfunction, and so forth.

Examples[edit]

Clinical testing[edit]

MK-2866 also known as Ostarine or Enobosarm

• Enobosarm (Ostarine, MK-2866, GTx-024, S-22) – One of the most popular SARMs, 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.

Pre-clinical[edit]

• AC-262,356
• LGD-2226 – Affects both muscle and bone
• LGD-3303
• 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
• RAD140 (Testolone)

Abandoned drug candidates[edit]

• 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
• LG-121071
• TFM-4AS-1
• YK-11

Availability[edit]

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 rights of the patent holders of the compounds. In 2017 it was found that many of the supplements being sold claiming to be SARMs do not actually contain the chemical in question. In reality, only 52% of the products contained any traces of SARMs at all.

In October 2017, the Food and Drug Administration issued warning letters to three supplement companies notifying them that SARMS are classed as unapproved drugs and can cause potential adverse side effects associated including cardiovascular and liver damage.

Use in sports[edit]

In 2015, quarterback of the Florida Gators, Will Grier, allegedly tested positive for Ligandrol, a claim that the University of Florida denies.

In 2017, Joakim Noah was banned for twenty games by the NBA for testing positive for Ligandrol.

Sean O'Malley, the American mixed martial artist who competes in the Bantamweight division of Ultimate Fighting Championship, was temporarily suspended by the Nevada State Athletic Commission in June 2019 after his sample tested positive for Enobosarm ahead of his fight against Marlon Vera at UFC 239 on July 6 in Las Vegas.

In July 2019, tennis player Beatriz Haddad Maia from Brazil received a provisional suspension after she tested positive for selective androgen receptor modulators.

Shayna Jack, the Australian swimmer, was forced to withdraw in July 2019 from the national squad before the world championships in Gwangju, South Korea after she tested positive for Ligandrol.