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'''Ostarine''' is an investigational [[selective androgen receptor modulator]] (SARM) developed by GTx Inc for treatment of conditions such as [[muscle]] wasting and [[osteoporosis]].<ref>[http://www.google.com/patents?id=zmSBAAAAEBAJ&dq=6569896 James T. Dalton, Duane D. Miller, Donghua Yin, Yali He. Selective androgen receptor modulators and methods of use thereof. US Patent 6569896]</ref> Treatment with exogenous [[testosterone]] is effective in counteracting these symptoms but is associated with a range of side effects, the most serious of which is enlargement of the [[prostate gland]], which can lead to [[benign prostatic hypertrophy]] and even [[prostate cancer]]. This means there is a clinical need for selective androgen receptor modulators, which produce [[anabolic]] effects in some tissues such as muscle and bone, but without stimulating androgen receptors in the prostate.<ref>Gao W, Dalton JT. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs). ''Drug Discovery Today''. 2007 Mar;12(5-6):241-8. PMID 17331889</ref> Ostarine was one of the first SARMs to be developed,<ref>Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT. Pharmacodynamics of selective androgen receptor modulators. ''Journal of Pharmacology and Experimental Therapeutics''. 2003 Mar;304(3):1334-40. PMID 12604714</ref> using the non-steroidal androgen antagonist [[bicalutamide]] as a lead compound.<ref>Chen J, Kim J, Dalton JT. Discovery and therapeutic promise of selective androgen receptor modulators. ''Molecular Interventions''. 2005 Jun;5(3):173-88. PMID 15994457</ref>
'''Ostarine''' is an investigational [[selective androgen receptor modulator]] (SARM) from GTx Inx, for treatment of conditions such as [[muscle]] wasting and [[osteoporosis]], formerly under development by [[Merck & Company]] and also known as MK-2866.<ref>[http://www.google.com/patents?id=zmSBAAAAEBAJ&dq=6569896 James T. Dalton, Duane D. Miller, Donghua Yin, Yali He. Selective androgen receptor modulators and methods of use thereof. US Patent 6569896]</ref> On March 2, 2010, Merck announced via its 10K annual filing to the SEC that "Merck has discontinued internal development of MK-2866 (which is a SARM) under this agreement, and is currently discussing next steps with GTx."<ref>[http://www.sec.gov/Archives/edgar/data/310158/000095012310018679/y81622e10vk.htm 10-K Merck & Company, March 2, 2010] </ref>
Treatment with exogenous [[testosterone]] is effective in counteracting these symptoms but is associated with a range of side effects, the most serious of which is enlargement of the [[prostate gland]], which can lead to [[benign prostatic hypertrophy]] and theoretically increase the growth of pre-exisiting [[prostate cancer]]. This means there is a clinical need for selective androgen receptor modulators, which produce [[anabolic]] effects in some tissues such as muscle and bone, but without stimulating androgen receptors in the prostate.<ref>Gao W, Dalton JT. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs). ''Drug Discovery Today''. 2007 Mar;12(5-6):241-8. PMID 17331889</ref> Ostarine was one of the first SARMs to be developed,<ref>Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT. Pharmacodynamics of selective androgen receptor modulators. ''Journal of Pharmacology and Experimental Therapeutics''. 2003 Mar;304(3):1334-40. PMID 12604714</ref> using the non-steroidal androgen antagonist [[bicalutamide]] as a lead compound.<ref>Chen J, Kim J, Dalton JT. Discovery and therapeutic promise of selective androgen receptor modulators. ''Molecular Interventions''. 2005 Jun;5(3):173-88. PMID 15994457</ref>


Ostarine is an orally active, potent and selective agonist for androgen receptors which was shown in animal studies to have [[anabolic]] effects in both muscle and bone tissue, but with no measurable effect on [[lutenizing hormone]] or [[follicle-stimulating hormone]] levels at the dose range tested, although it did increase [[prostate gland|prostate]] weight, with an androgenic potency around 1/3rd of its anabolic potency. It was shown ''in vitro'' to increase the ratio of [[osteoblast]] formation from bone marrow osteoprogenitor cells, and reduced the number of new [[osteoclast]]s formed. It produced dose-dependent increases in bone mineral density and mechanical strength ''in vivo'', as well as decreasing body fat and increasing lean body mass.<ref>Kearbey JD, Gao W, Narayanan R, Fisher SJ, Wu D, Miller DD, Dalton JT. Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. ''Pharmaceutical Research''. 2007 Feb;24(2):328-35. PMID 17063395</ref> Human trials have shown evidence of promising efficacy, with a long half-life in humans of 24 hours.<ref>Gao W, Kim J, Dalton JT. Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands. ''Pharmaceutical Research''. 2006 Aug;23(8):1641-58. PMID 16841196</ref> Ostarine has completed a human proof of concept trial in normal elderly subjects with positive results of safety and increase in lean body mass as measured by [[DEXA]], as well as a secondary endpoint of an increase in power and time to ascent in a 12 step stair climb functional test <ref>[http://www.medicalnewstoday.com/articles/58552.php GTx Announces That Ostarine Achieved Primary Endpoint Of Lean Body Mass And A Secondary Endpoint Of Improved Functional Performance]</ref>. A second trial, this time a Ph2b in patients with cancer [[cachexia]], reproduced the positive results of the PoC trial, with safety and increase in lean body mass as measured by [[DEXA]], as well as one of the secondary endpoints being the 12 step stair climb, however this study failed to achieve the other two endpoints of a statistical difference in 6 minute walk distance, or in grip strength.
Ostarine is an orally active, potent and selective agonist for androgen receptors which was shown in animal studies to have [[anabolic]] effects in both muscle and bone tissue, but with no measurable effect on [[lutenizing hormone]] or [[follicle-stimulating hormone]] levels at the dose range tested, although it did increase [[prostate gland|prostate]] weight, with an androgenic potency around 1/3rd of its anabolic potency. It was shown ''in vitro'' to increase the ratio of [[osteoblast]] formation from bone marrow osteoprogenitor cells, and reduced the number of new [[osteoclast]]s formed. It produced dose-dependent increases in bone mineral density and mechanical strength ''in vivo'', as well as decreasing body fat and increasing lean body mass.<ref>Kearbey JD, Gao W, Narayanan R, Fisher SJ, Wu D, Miller DD, Dalton JT. Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. ''Pharmaceutical Research''. 2007 Feb;24(2):328-35. PMID 17063395</ref> Human trials have shown evidence of promising efficacy, with a long half-life in humans of 24 hours.<ref>Gao W, Kim J, Dalton JT. Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands. ''Pharmaceutical Research''. 2006 Aug;23(8):1641-58. PMID 16841196</ref> Ostarine has completed a human proof of concept trial in normal elderly subjects with positive results of safety and increase in lean body mass as measured by [[DEXA]], as well as a secondary endpoint of an increase in power and time to ascent in a 12 step stair climb functional test <ref>[http://www.medicalnewstoday.com/articles/58552.php GTx Announces That Ostarine Achieved Primary Endpoint Of Lean Body Mass And A Secondary Endpoint Of Improved Functional Performance]</ref>. A second trial, this time a Ph2b in patients with cancer [[cachexia]], reproduced the positive results of the PoC trial, with safety and increase in lean body mass as measured by [[DEXA]], as well as one of the secondary endpoints being the 12 step stair climb, however this study failed to achieve the other two endpoints of a statistical difference in 6 minute walk distance, or in grip strength.

Revision as of 20:21, 2 March 2010

Enobosarm
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • Investigational new drug
Pharmacokinetic data
Elimination half-life24 hours
Identifiers
  • The structure shown above is wrong. Andarine has the acetamido substituent. (S)-3-(4-xxx-phenoxy)-2-hydroxy-2-methyl-N-(4-xxx-3-trifluoromethyl-phenyl)-propionamide
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC18H18F3N3O3
Molar massg/mol g·mol−1
3D model (JSmol)
Melting point70 to 74 °C (158 to 165 °F)
  • O=N(=O)c1ccc(cc1C(F)(F)F)NC(=O)C(O)(C)COc2ccc(cc2)NC(C)=O

Ostarine is an investigational selective androgen receptor modulator (SARM) from GTx Inx, for treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merck & Company and also known as MK-2866.[1] On March 2, 2010, Merck announced via its 10K annual filing to the SEC that "Merck has discontinued internal development of MK-2866 (which is a SARM) under this agreement, and is currently discussing next steps with GTx."[2]

Treatment with exogenous testosterone is effective in counteracting these symptoms but is associated with a range of side effects, the most serious of which is enlargement of the prostate gland, which can lead to benign prostatic hypertrophy and theoretically increase the growth of pre-exisiting prostate cancer. This means there is a clinical need for selective androgen receptor modulators, which produce anabolic effects in some tissues such as muscle and bone, but without stimulating androgen receptors in the prostate.[3] Ostarine was one of the first SARMs to be developed,[4] using the non-steroidal androgen antagonist bicalutamide as a lead compound.[5]

Ostarine is an orally active, potent and selective agonist for androgen receptors which was shown in animal studies to have anabolic effects in both muscle and bone tissue, but with no measurable effect on lutenizing hormone or follicle-stimulating hormone levels at the dose range tested, although it did increase prostate weight, with an androgenic potency around 1/3rd of its anabolic potency. It was shown in vitro to increase the ratio of osteoblast formation from bone marrow osteoprogenitor cells, and reduced the number of new osteoclasts formed. It produced dose-dependent increases in bone mineral density and mechanical strength in vivo, as well as decreasing body fat and increasing lean body mass.[6] Human trials have shown evidence of promising efficacy, with a long half-life in humans of 24 hours.[7] Ostarine has completed a human proof of concept trial in normal elderly subjects with positive results of safety and increase in lean body mass as measured by DEXA, as well as a secondary endpoint of an increase in power and time to ascent in a 12 step stair climb functional test [8]. A second trial, this time a Ph2b in patients with cancer cachexia, reproduced the positive results of the PoC trial, with safety and increase in lean body mass as measured by DEXA, as well as one of the secondary endpoints being the 12 step stair climb, however this study failed to achieve the other two endpoints of a statistical difference in 6 minute walk distance, or in grip strength.

SARMs are expected to have attractive features of performance enhancement, not only in meeting unmet medical needs for patients suffering from serious disability due to diminished muscle capacity, but also for athletes seeking increase physical stamina and fitness, as theoretically SARMs will produce effects similar to anabolic steroids but with significantly less side effects. For this reason, SARMs have been added to the prohibited substance list for athletic competition by the World Anti-Doping Agency, which also includes other agents with performance enhancement characteristics, including US DEA controlled substances such as testosterone and anabolic steroids, but also non DEA controlled substances like EPO and insulin, aromatase inhibitors and SERMs. Blood tests for all known SARMs are currently being developed.[9][10]

References

  1. ^ James T. Dalton, Duane D. Miller, Donghua Yin, Yali He. Selective androgen receptor modulators and methods of use thereof. US Patent 6569896
  2. ^ 10-K Merck & Company, March 2, 2010
  3. ^ Gao W, Dalton JT. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs). Drug Discovery Today. 2007 Mar;12(5-6):241-8. PMID 17331889
  4. ^ Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT. Pharmacodynamics of selective androgen receptor modulators. Journal of Pharmacology and Experimental Therapeutics. 2003 Mar;304(3):1334-40. PMID 12604714
  5. ^ Chen J, Kim J, Dalton JT. Discovery and therapeutic promise of selective androgen receptor modulators. Molecular Interventions. 2005 Jun;5(3):173-88. PMID 15994457
  6. ^ Kearbey JD, Gao W, Narayanan R, Fisher SJ, Wu D, Miller DD, Dalton JT. Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. Pharmaceutical Research. 2007 Feb;24(2):328-35. PMID 17063395
  7. ^ Gao W, Kim J, Dalton JT. Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands. Pharmaceutical Research. 2006 Aug;23(8):1641-58. PMID 16841196
  8. ^ GTx Announces That Ostarine Achieved Primary Endpoint Of Lean Body Mass And A Secondary Endpoint Of Improved Functional Performance
  9. ^ Thevis M, Kohler M, Schlörer N, Kamber M, Kühn A, Linscheid MW, Schänzer W. Mass spectrometry of hydantoin-derived selective androgen receptor modulators. Journal of Mass Spectrometry. 2008 May;43(5):639-50. PMID 18095383
  10. ^ Thevis M, Kohler M, Thomas A, Maurer J, Schlörer N, Kamber M, Schänzer W. Determination of benzimidazole- and bicyclic hydantoin-derived selective androgen receptor antagonists and agonists in human urine using LC-MS/MS. Analytical and Bioanalytical Chemistry. 2008 May;391(1):251-61. PMID 18270691


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