| 词条 | Selective androgen receptor modulator |
| 释义 |
| Image = Ostarine.svg | Alt = | Caption = Enobosarm (ostarine), a nonsteroidal {{abbr|SARM|selective androgen receptor modulator}} which is or was under investigation for potential medical use. | Width = 250px | Synonyms = Partial androgens | Use = Hypogonadism; Osteopenia; Osteoporosis; Sarcopenia; Cachexia; | ATC_prefix = | Biological_target = Androgen receptor | Chemical_class = Steroidal; Nonsteroidal | Drugs.com = | Consumer_Reports = | medicinenet = | rxlist = | MeshID = }} 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 but be much more selective in their action,[1] allowing them to be used for more uses than the relatively limited legitimate uses of anabolic steroids. Comparison to testosteroneCurrently 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.[2][3][4] 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.[6][7][8] Selectivity in menFor 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.[9] Men who want muscles for a more desirable physical appearance can also use SARMs, they would target muscle growth in a safer way.[10] Selectivity in womenA 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 gender characteristics (virilization), increased LDL/HDL ratios, liver dysfunction, and so forth.[11] ExamplesClinical testing
Pre-clinical
Abandoned drug candidates
AvailabilityIn 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.[21] In 2017 it was found that many of the supplements being sold claiming to be SARMs do not actually contain the chemical in question.[22] 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.[23] In 2017, Joakim Noah was banned for twenty games by the NBA for testing positive for LGD-4033.[24] 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.[25] See also
References1. ^{{cite journal | vauthors = Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, Hwang DJ, Dalton JT, Miller DD | title = Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 12 | pages = 3597–617 | date = June 2009 | pmid = 19432422 | doi = 10.1021/jm900280m }} {{Androgens and antiandrogens}}{{Androgen receptor modulators}}2. ^{{cite journal | vauthors = Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT | title = Pharmacodynamics of selective androgen receptor modulators | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 304 | issue = 3 | pages = 1334–40 | date = March 2003 | pmid = 12604714 | pmc = 2040238 | doi = 10.1124/jpet.102.040840 }} 3. ^{{cite journal | vauthors = Hanada K, Furuya K, Yamamoto N, Nejishima H, Ichikawa K, Nakamura T, Miyakawa M, Amano S, Sumita Y, Oguro N | title = Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis | journal = Biological & Pharmaceutical Bulletin | volume = 26 | issue = 11 | pages = 1563–9 | date = November 2003 | pmid = 14600402 | doi = 10.1248/bpb.26.1563 }} 4. ^{{cite journal | vauthors = Ostrowski J, Kuhns JE, Lupisella JA, Manfredi MC, Beehler BC, Krystek SR, Bi Y, Sun C, Seethala R, Golla R, Sleph PG, Fura A, An Y, Kish KF, Sack JS, Mookhtiar KA, Grover GJ, Hamann LG | title = Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats | journal = Endocrinology | volume = 148 | issue = 1 | pages = 4–12 | date = January 2007 | pmid = 17008401 | doi = 10.1210/en.2006-0843 }} 5. ^{{Citation|last=Aethyta|title=English: Structure of RAD140.|date=2015-10-19|url=https://commons.wikimedia.org/wiki/File:RAD140_structure.png|accessdate=2017-09-21}} 6. ^{{cite journal | vauthors = Manfredi MC, Bi Y, Nirschl AA, Sutton JC, Seethala R, Golla R, Beehler BC, Sleph PG, Grover GJ, Ostrowski J, Hamann LG | title = Synthesis and SAR of tetrahydropyrrolo[1,2-b][1,2,5]thiadiazol-2(3H)-one 1,1-dioxide analogues as highly potent selective androgen receptor modulators | journal = Bioorganic & Medicinal Chemistry Letters | volume = 17 | issue = 16 | pages = 4487–90 | date = August 2007 | pmid = 17574413 | doi = 10.1016/j.bmcl.2007.06.007 }} 7. ^{{cite journal | vauthors = Zhang X, Li X, Allan GF, Sbriscia T, Linton O, Lundeen SG, Sui Z | title = Design, synthesis, and in vivo SAR of a novel series of pyrazolines as potent selective androgen receptor modulators | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 16 | pages = 3857–69 | date = August 2007 | pmid = 17636947 | doi = 10.1021/jm0613976 }} 8. ^{{cite journal | vauthors = Long YO, Higuchi RI, Caferro TR, Lau TL, Wu M, Cummings ML, Martinborough EA, Marschke KB, Chang WY, López FJ, Karanewsky DS, Zhi L | title = Selective androgen receptor modulators based on a series of 7H-[1,4]oxazino[3,2-g]quinolin-7-ones with improved in vivo activity | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 9 | pages = 2967–71 | date = May 2008 | pmid = 18400499 | doi = 10.1016/j.bmcl.2008.03.062 }} 9. ^{{cite journal | vauthors = Ke HZ, Wang XN, O'Malley J, Lefker B, Thompson DD | title = Selective androgen receptor modulators--prospects for emerging therapy in osteoporosis? | journal = Journal of Musculoskeletal & Neuronal Interactions | volume = 5 | issue = 4 | pages = 355 | year = 2005 | pmid = 16340136 | doi = | url = http://www.ismni.org/jmni/pdf/22/23THOMPSON.pdf }} 10. ^{{Cite web|url=https://legionathletics.com/sarms/|title=This Is Everything You Need to Know About SARMs|date=2019-01-03|website=Legion Athletics|language=en-US|access-date=2019-02-10}} 11. ^{{cite journal | vauthors = Negro-Vilar A | title = Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 84 | issue = 10 | pages = 3459–62 | date = October 1999 | pmid = 10522980 | doi = 10.1210/jc.84.10.3459 }} 12. ^{{cite journal |author=M.S. Steiner|title=Effect of GTx-024, a selective androgen receptor modulator (SARM), on stair climb and quality of life (QOL) in patients with cancer cachexia |journal= J Clin Oncol|volume=28|issue=1534|date=June 2010|url=http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=52947 |display-authors=etal}} 13. ^{{cite journal | vauthors = Piu F, Gardell LR, Son T, Schlienger N, Lund BW, Schiffer HH, Vanover KE, Davis RE, Olsson R, Bradley SR | title = Pharmacological characterization of AC-262536, a novel selective androgen receptor modulator | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 109 | issue = 1-2 | pages = 129–37 | date = March 2008 | pmid = 18164613 | doi = 10.1016/j.jsbmb.2007.11.001 }} 14. ^{{cite journal | vauthors = Vajda EG, López FJ, Rix P, Hill R, Chen Y, Lee KJ, O'Brien Z, Chang WY, Meglasson MD, Lee YH | title = Pharmacokinetics and pharmacodynamics of LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an orally available nonsteroidal-selective androgen receptor modulator | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 328 | issue = 2 | pages = 663–70 | date = February 2009 | pmid = 19017848 | doi = 10.1124/jpet.108.146811 }} 15. ^{{cite journal | vauthors = Jones A, Chen J, Hwang DJ, Miller DD, Dalton JT | title = Preclinical characterization of a (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide: a selective androgen receptor modulator for hormonal male contraception | journal = Endocrinology | volume = 150 | issue = 1 | pages = 385–95 | date = January 2009 | pmid = 18772237 | pmc = 2630904 | doi = 10.1210/en.2008-0674 }} 16. ^{{cite journal | vauthors = Miller CP, Shomali M, Lyttle CR, O'Dea LS, Herendeen H, Gallacher K, Paquin D, Compton DR, Sahoo B, Kerrigan SA, Burge MS, Nickels M, Green JL, Katzenellenbogen JA, Tchesnokov A, Hattersley G | title = Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140 | journal = ACS Medicinal Chemistry Letters | volume = 2 | issue = 2 | pages = 124–9 | date = February 2011 | pmid = 24900290 | doi = 10.1021/ml1002508 | pmc=4018048}} 17. ^{{cite journal | vauthors = Yin D, Xu H, He Y, Kirkovsky LI, Miller DD, Dalton JT | title = Pharmacology, pharmacokinetics, and metabolism of acetothiolutamide, a novel nonsteroidal agonist for the androgen receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 304 | issue = 3 | pages = 1323–33 | date = March 2003 | pmid = 12604713 | doi = 10.1124/jpet.102.040832 | pmc = 2040235 }} 18. ^{{cite journal | vauthors = Kearbey JD, Gao W, Narayanan R, Fisher SJ, Wu D, Miller DD, Dalton JT | title = Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats | journal = Pharmaceutical Research | volume = 24 | issue = 2 | pages = 328–35 | date = February 2007 | pmid = 17063395 | pmc = 2039878 | doi = 10.1007/s11095-006-9152-9 }} 19. ^{{cite journal | vauthors = Hamann LG, Mani NS, Davis RL, Wang XN, Marschke KB, Jones TK | title = Discovery of a potent, orally active, nonsteroidal androgen receptor agonist: 4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl)-8-pyridono[5,6-g]- quinoline (LG121071) | journal = Journal of Medicinal Chemistry | volume = 42 | issue = 2 | pages = 210–2 | date = January 1999 | pmid = 9925725 | doi = 10.1021/jm9806648 }} 20. ^{{cite journal | vauthors = Gao W, Kim J, Dalton JT | title = Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands | journal = Pharmaceutical Research | volume = 23 | issue = 8 | pages = 1641–58 | date = August 2006 | pmid = 16841196 | doi = 10.1007/s11095-006-9024-3 | pmc=2072875}} 21. ^{{cite web|title=SARMs: The Controversial Muscle-Builders of 2015|url=https://blog.priceplow.com/sarms|website=The PricePlow Blog|accessdate=20 October 2015}} 22. ^{{cite journal|last1=Van Wagoner|first1=Ryan M.|last2=Eichner|first2=Amy|last3=Bhasin|first3=Shalender|last4=Deuster|first4=Patricia A.|last5=Eichner|first5=Daniel|title=Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet|journal=JAMA|date=28 November 2017|volume=318|issue=20|pages=2004|doi=10.1001/jama.2017.17069}} 23. ^{{cite news |last1=Trahan |first1= Kevin |title= Florida starting QB Will Grier suspended for at least 2015 after taking banned substance |url= https://www.sbnation.com/college-football/2015/10/12/9510055/florida-qb-will-grier-suspended-for-rest-of-2015-due-to-ncaa |accessdate= 20 October 2015 |website= SBnation.com |date= 12 October 2015}} 24. ^{{cite news | url = https://www.nytimes.com/2017/03/25/sports/basketball/knicks-joakim-noah-suspended-for-failing-a-doping-test.html | publisher = New York Times | date = March 25, 2017 | title = Knicks’ Joakim Noah Suspended for Failing a Doping Test}} 25. ^{{Cite web|url=https://www.fda.gov/newsevents/newsroom/fdainbrief/ucm583021.htm|title=FDA In Brief - FDA In Brief: FDA warns against using SARMs in body-building products|last=Commissioner|first=Office of the|website=www.fda.gov|language=en|access-date=2018-09-03}} 2 : Selective androgen receptor modulators|World Anti-Doping Agency prohibited substances |
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