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MK-0773

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MK-0773
Clinical data
Other namesPF-05314882; N-(3H-Imidazo(4,5-b)pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide
Routes of
administration		By mouth
Identifiers
  • (1S,3aS,3bS,5aR,9aS,9bS,11aS)-8-Fluoro-N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,9b,10,11-decahydro-1H-indeno[5,4-f]quinoline-1-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H34FN5O2
Molar mass479.600 g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2C(=O)NCC4=NC5=C(N4)C=CC=N5)CC[C@@H]6[C@@]3(C=C(C(=O)N6C)F)C
  • InChI=1S/C27H34FN5O2/c1-26-11-10-17-15(6-9-21-27(17,2)13-19(28)25(35)33(21)3)16(26)7-8-18(26)24(34)30-14-22-31-20-5-4-12-29-23(20)32-22/h4-5,12-13,15-18,21H,6-11,14H2,1-3H3,(H,30,34)(H,29,31,32)/t15-,16-,17-,18+,21+,26-,27+/m0/s1
  • Key:GBEUKTWTUSPHEE-JWJWXJQQSA-N

MK-0773, also known as PF-05314882, is a steroidal, orally active selective androgen receptor modulator (SARM) that was under development by Merck and GTx for the treatment of sarcopenia (loss of muscle mass) in women and men.[1][2][3] Clinical trials for sarcopenia began in late 2007 but the collaboration between Merck and GTx ended in early 2010 and GTx terminated development of MK-0773 shortly thereafter.[2] MK-0773 was developed as a more advanced version of the related compound TFM-4AS-1.[4]

MK-0773 is a 4-azasteroid[5] and a potent and selective agonist of the androgen receptor (AR).[1] It binds to the AR with an EC50 of 6.6 nM and is a partial agonist in transactivation modulation of the AR with an IP of 25 nM and Emax of 78% and has a TRAF2 Emax of 29% and an N/C interaction (virilization-related) counterscreen assay Emax of 2%.[1] That is, it produces promoter activation but induces the N/C interaction almost negligibly.[1] MK-0773 is reportedly four times as potent as testosterone as an agonist of the AR.[2] The drug is selective and does not bind to other steroid hormone receptors such as the progesterone receptor or glucocorticoid receptor and shows no significant inhibition of 5α-reductase (IC50 > 10 μM).[1] In addition, it is non-aromatizable and hence has no potential for estrogenic effects or side effects, like gynecomastia.[6] MK-0773 had similar effects on lipid metabolism relative to DHT, including a decrease in total cholesterol and high-density lipoprotein (HDL) of a similar magnitude.[1]

MK-0773 shows tissue-selective androgenic effects in vivo in animals.[1] It increases lean body mass with maximal anabolic effects that are approximately 80% of those of dihydrotestosterone (DHT).[1] However, it had less than 5% of the effect of DHT on uterine weight, about 30 to 50% of the increase of sebaceous gland area induced by DHT, and increased the weight of the seminal vesicles by 12% of that of DHT at the highest dosage assessed.[4][1] It had similarly reduced effects on the prostate gland.[1] No significant increase in gene expression of six candidate genes related to virilization was observed.[7] As such, MK-0773 shows a profile of an anabolic SARM with limited effects on sebaceous glands and reproductive tissues in animals and a reduced propensity for virilization.[1]

In human clinical studies, MK-0773 produced anabolism in women and men while producing no or very low effects on sebaceous glands, the endometrium, or the prostate gland after 12 weeks of treatment.[1][7][8][9] A decrease in total cholesterol and HDL was also observed in the clinical studies.[1] MK-0773 produced a significant increase in lean body mass in elderly (≥65 years of age) women with sarcopenia and moderate physical dysfunction.[10][11][12] It also increased muscle strength relative to placebo but this failed to reach statistical significance.[10][12] MK-0773 has been associated with elevated liver enzymes in clinical studies.[10]

See also

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References

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  1. ^ a b c d e f g h i j k l m Schmidt A, Kimmel DB, Bai C, Scafonas A, Rutledge S, Vogel RL, et al. (May 2010). "Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology". The Journal of Biological Chemistry. 285 (22): 17054–17064. doi:10.1074/jbc.M109.099002. PMC 2878020. PMID 20356837.
  2. ^ a b c Newton DE (26 November 2013). "Problems, Controversies, and Solutions". Steroids and Doping in Sports: A Reference Handbook: A Reference Handbook. ABC-CLIO. pp. 85–. ISBN 978-1-61069-314-1.
  3. ^ "MK 0773". AdisInsight. Springer Nature Switzerland AG.
  4. ^ a b Zhang X, Sui Z (February 2013). "Deciphering the selective androgen receptor modulators paradigm". Expert Opin Drug Discov. 8 (2): 191–218. doi:10.1517/17460441.2013.741582. PMID 23231475.
  5. ^ Lagojda A, Kuehne D, Krug O, Thomas A, Wigger T, Karst U, et al. (2016). "Identification of selected in vitro generated phase-I metabolites of the steroidal selective androgen receptor modulator MK-0773 for doping control purposes". European Journal of Mass Spectrometry. 22 (2): 49–59. doi:10.1255/ejms.1415. PMID 27419898. S2CID 207191784.
  6. ^ Stoch SA, Friedman EJ, Zhou Y, Zhu H, Larson P, Binkowitz B, et al. (June 2010). "Biomarkers of Bone Metabolism and Serum Free Estradiol (E2) Levels in Medically Castrated Older Men Treated with MK-0773 (MK), Testosterone (T), or Placebo (PBO) for 12 Weeks". Endocrine Reviews. 31 (3): S48.
  7. ^ a b Stoch SA (31 January 2011). "Bone Disorders: Translational Medicine Case Studies". In Littman BH, Krishna R (eds.). Translational Medicine and Drug Discovery. Cambridge University Press. pp. 136–. doi:10.1017/CBO9780511976087.007. ISBN 978-1-139-49872-2.
  8. ^ Stoch SA, Friedman EJ, Zhu H, Xu Y, Wong P, Chappell DL, et al. (2008). A 12-week pharmacokinetic and pharmacodynamic (PD) study of MK-0773 in healthy postmenopausal (PMP) subjects. The Endocrine Society 90th Annual Meeting, June 12–15, San Francisco, CA. Abst. OR35–33.
  9. ^ Stoch SA, et al. (2009) 91st Annual Meeting of the Endocrine Society, Washington, D.C. Abst. S21–24.
  10. ^ a b c Papanicolaou DA, Ather SN, Zhu H, Zhou Y, Lutkiewicz J, Scott BB, Chandler J (2013). "A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia". The Journal of Nutrition, Health & Aging. 17 (6): 533–543. doi:10.1007/s12603-013-0335-x. PMID 23732550. S2CID 42439768.
  11. ^ Basualto-Alarcón C, Varela D, Duran J, Maass R, Estrada M (2014). "Sarcopenia and Androgens: A Link between Pathology and Treatment". Frontiers in Endocrinology. 5: 217. doi:10.3389/fendo.2014.00217. ISBN 9781771883719. PMC 4270249. PMID 25566189.
  12. ^ a b MacDonald N (23 April 2015). "Weight and Appetite Loss in Cancer". In Holland JC, Breitbart WS, Jacobsen PB, Butow PN, Loscalzo MJ, McCorkle R (eds.). Psycho-Oncology. Oxford University Press. pp. 242–. ISBN 978-0-19-936331-5.
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