MK-0773
Abandoned drug
From Wikipedia, the free encyclopedia
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]
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| Other names | PF-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 |
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| Formula | C27H34FN5O2 |
| Molar mass | 479.600 g·mol−1 |
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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]
MK-0773 has been encountered as a novel designer drug.[13]