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Ostarine ((2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide) (also known as GTx-024 and MK-2866) is an investigational selective androgen receptor modulator (SARM) from GTX, Inc for treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merck & Company.[1]
[edit] Structure
According to a recent paper authored by GTx, "Readers are cautioned to note that the name Ostarine is often mistakenly linked to the chemical structure of [S-4], which is also known as andarine. The chemical structure of Ostarine has not been publicly disclosed."[2] While GTx has not formally disclosed the structure of Ostarine, the chemical composition of Ostarine is revealed in patent databases such the WIPO[3] and discussed by Zhang et al., 2009 in the primary literature.[4] Various SARM chemotypes exist (aryl propionamides, quinolines, quinolinones, bicyclic hydantoins), though aryl propionamides such as Ostarine, Andarine/S-4, and S-23 represent some of the most advanced putative therapeutics under investigation.[5] In terms of atom connectivity, Ostarine differs from Andarine by cyano substitutions on the phenyl rings as it replaces both the nitro and acetamido moieties.
[edit] Clinical trials
In December 2006, GTx completed a 3 month Phase II double-blind, randomized, placebo-controlled clinical trial in 120 subjects (60 elderly men and 60 postmenopausal women). Ostarine treatment resulted in a dose-dependent increase in lean body mass (LBM), with those taking the highest dose of 3 mg per day showing an average LBM increase of 1.4 kg (3.1 lbs) compared to those who received placebo. The Ostarine treatment also resulted in improvement in muscle function (performance) in a 12 stair climb test measuring speed and power. Ostarine had a favorable safety profile, with no serious adverse events reported. Ostarine also exhibited tissue selectivity with beneficial effects on lean body mass and performance and with no apparent change in measurements of serum PSA, sebum production or serum LH.[6]
In October 2008, GTx announced topline results of the Phase II trial evaluating Ostarine in patients with cancer cachexia. The clinical trial enrolled 159 cancer patients (average age of 66 years) with non-small cell lung cancer, colorectal cancer, non-Hodgkin lymphoma, chronic lymphocytic leukemia or breast cancer at 35 sites in the U.S. and Argentina. Participants were randomized to receive placebo, 1 mg or 3 mg oral capsule of Ostarine once daily for 16 weeks. Average reported weight loss prior to entry among all subjects was 8.8%. Subjects were allowed to have standard chemotherapy during the trial. The study met its primary endpoint of absolute change in total lean body mass (muscle) compared to placebo and the secondary endpoint of muscle function (performance). The incidence of serious adverse events, deaths and tumor progression were similar among placebo and the treatment arms. The most common side effects reported among all subjects in the trial were fatigue, anemia, nausea and diarrhea.[6]
GTx and Merck had clinical development plans to evaluate Ostarine for the treatment of muscle loss in patients with COPD and for the treatment of chronic sarcopenia. They had a goal of initiating an Ostarine Phase II COPD clinical trial in the first quarter of 2010 and an Ostarine Phase IIb chronic sarcopenia clinical trial in 2010.[7]
References
^ James T. Dalton, Duane D. Miller, Donghua Yin, Yali He. Selective androgen receptor modulators and methods of use thereof. US Patent 6569896
^ Mohler ML, Bohl CE, Jones A, et al. (June 2009). "Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit". J. Med. Chem. 52 (12): 3597–617. doi:10.1021/jm900280m. PMID 19432422.
^ WO application 2008127717, James T. Dalton and Duane D. Miller, "Selective Androgen Receptor Modulators for Treating Diabetes", published Oct 23, 2008, assigned to University of Tennessee Research Foundation, James T. Dalton, and Duane D. Miller
^ Zhang X, Lanter JC, Sui Z (September 2009). "Recent advances in the development of selective androgen receptor modulators". Expert Opin Ther Pat 19 (9): 1239–58. doi:10.1517/13543770902994397. PMID 19505196.
^ Jones A, Chen J, Hwang DJ, Miller DD, Dalton JT (January 2009). "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". Endocrinology 150 (1): 385–95. doi:10.1210/en.2008-0674. PMC 2630904. PMID 18772237.
^ a b GTx. Ostarine
^ GTX INC /DE/ - FORM 10-Q - November 9, 2009
[edit] Structure
According to a recent paper authored by GTx, "Readers are cautioned to note that the name Ostarine is often mistakenly linked to the chemical structure of [S-4], which is also known as andarine. The chemical structure of Ostarine has not been publicly disclosed."[2] While GTx has not formally disclosed the structure of Ostarine, the chemical composition of Ostarine is revealed in patent databases such the WIPO[3] and discussed by Zhang et al., 2009 in the primary literature.[4] Various SARM chemotypes exist (aryl propionamides, quinolines, quinolinones, bicyclic hydantoins), though aryl propionamides such as Ostarine, Andarine/S-4, and S-23 represent some of the most advanced putative therapeutics under investigation.[5] In terms of atom connectivity, Ostarine differs from Andarine by cyano substitutions on the phenyl rings as it replaces both the nitro and acetamido moieties.
[edit] Clinical trials
In December 2006, GTx completed a 3 month Phase II double-blind, randomized, placebo-controlled clinical trial in 120 subjects (60 elderly men and 60 postmenopausal women). Ostarine treatment resulted in a dose-dependent increase in lean body mass (LBM), with those taking the highest dose of 3 mg per day showing an average LBM increase of 1.4 kg (3.1 lbs) compared to those who received placebo. The Ostarine treatment also resulted in improvement in muscle function (performance) in a 12 stair climb test measuring speed and power. Ostarine had a favorable safety profile, with no serious adverse events reported. Ostarine also exhibited tissue selectivity with beneficial effects on lean body mass and performance and with no apparent change in measurements of serum PSA, sebum production or serum LH.[6]
In October 2008, GTx announced topline results of the Phase II trial evaluating Ostarine in patients with cancer cachexia. The clinical trial enrolled 159 cancer patients (average age of 66 years) with non-small cell lung cancer, colorectal cancer, non-Hodgkin lymphoma, chronic lymphocytic leukemia or breast cancer at 35 sites in the U.S. and Argentina. Participants were randomized to receive placebo, 1 mg or 3 mg oral capsule of Ostarine once daily for 16 weeks. Average reported weight loss prior to entry among all subjects was 8.8%. Subjects were allowed to have standard chemotherapy during the trial. The study met its primary endpoint of absolute change in total lean body mass (muscle) compared to placebo and the secondary endpoint of muscle function (performance). The incidence of serious adverse events, deaths and tumor progression were similar among placebo and the treatment arms. The most common side effects reported among all subjects in the trial were fatigue, anemia, nausea and diarrhea.[6]
GTx and Merck had clinical development plans to evaluate Ostarine for the treatment of muscle loss in patients with COPD and for the treatment of chronic sarcopenia. They had a goal of initiating an Ostarine Phase II COPD clinical trial in the first quarter of 2010 and an Ostarine Phase IIb chronic sarcopenia clinical trial in 2010.[7]
References
^ James T. Dalton, Duane D. Miller, Donghua Yin, Yali He. Selective androgen receptor modulators and methods of use thereof. US Patent 6569896
^ Mohler ML, Bohl CE, Jones A, et al. (June 2009). "Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit". J. Med. Chem. 52 (12): 3597–617. doi:10.1021/jm900280m. PMID 19432422.
^ WO application 2008127717, James T. Dalton and Duane D. Miller, "Selective Androgen Receptor Modulators for Treating Diabetes", published Oct 23, 2008, assigned to University of Tennessee Research Foundation, James T. Dalton, and Duane D. Miller
^ Zhang X, Lanter JC, Sui Z (September 2009). "Recent advances in the development of selective androgen receptor modulators". Expert Opin Ther Pat 19 (9): 1239–58. doi:10.1517/13543770902994397. PMID 19505196.
^ Jones A, Chen J, Hwang DJ, Miller DD, Dalton JT (January 2009). "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". Endocrinology 150 (1): 385–95. doi:10.1210/en.2008-0674. PMC 2630904. PMID 18772237.
^ a b GTx. Ostarine
^ GTX INC /DE/ - FORM 10-Q - November 9, 2009
