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MK-0773, a NEW steroid from Merck?

JBerto

Active member
Some companies are still developing new steroids:

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Seems to be a new "old-fashioned" steroid with SARM-like effects

Any opinion about this?
 
I'll ask my girls cousin about it he works there in one of their labs dealing with this stuff
 
Steroidal SARM. Not much data for it. Just one paper so far:

J Biol Chem. 2010 May 28;285(22):17054-64. Epub 2010 Mar 31.

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.
Schmidt A, Kimmel DB, Bai C, Scafonas A, Rutledge S, Vogel RL, McElwee-Witmer S, Chen F, Nantermet PV, Kasparcova V, Leu CT, Zhang HZ, Duggan ME, Gentile MA, Hodor P, Pennypacker B, Masarachia P, Opas EE, Adamski SA, Cusick TE, Wang J, Mitchell HJ, Kim Y, Prueksaritanont T, Perkins JJ, Meissner RS, Hartman GD, Freedman LP, Harada S, Ray WJ.

Department of Molecular Endocrinology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

Abstract
Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

PMID: 20356837 [PubMed - indexed for MEDLINE]PMCID: PMC2878020 [Available on 2011/5/28]
 
PA's thoughts about this new roid:

very odd structure for an aas. first of all, the nitrogen group in the A-ring is something you see in steroidal 5ar inhibitors (the chemistry of which Merck are experts in). And the 17b- side chain is that of a 17b-carboxylic acid (another functional group found in 5ar inhibitors) that has been coupled by an amide bond to a bicyclic nitrogen containing ring system (this system has a name but its not coming to my head)

It seems apparent to me that Merck probably took their library of 5ar candidates (they made thousands of derivatives of finasteride type compounds during their efforts to find the perfect 5ar inhibitor) and then just tested them for AAS activity through some new fangeled in-vitro screening method. Apparently this one came out showing promise and i guess they then moved on to in-vivo testing and then now all the way to human testing and possible approval.

Its not unusual for drugs synthesized for other purposes to be screened for activity unrelated to the original purpose. This hit or miss technique has yielded some good drugs. As a matter of fact, back in 93 i interviewed at Merck in Rahway NJ and spoke to the chemist in charge of 5AR drug synthesis. He told me exactly what i am talking about, as in they synthesize tons of drugs and screen for activity and then those drugs go into storage often to be tested for other activity, just in case something unexpected and valueable pops up


this is the first AAS i have ever seen that did not have a 17b-oh, or a group that readily converts to a 17b-oh
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JBerto said:
PA's thoughts about this new roid:
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This is not unusual. In fact it is the norm. It is called high-throughput (or ultrahigh-throughput) screening where the companies library of accumulated compounds is tested against a desired target. Those compounds that exceed a threshold binding and activity profile are progressed through drug discovery to improve that desired actvity while removing whatever activity was originally designed into the molecule. The alternative, rationale drug design, is still used but is generally musc more expensive and time consuming.
 
new compound- is it oral? wet/dry?
 
schwellington said:
new compound- is it oral? wet/dry?
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Yes, it is oral. More info here:
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The Androgen Receptor (AR) is a transcription factor and an important member of the
superfamily of nuclear receptors. The AR is found in many tissues, including the
prostate, seminal vessel, skin, smooth muscle and bone. The AR is responsible for
mediating the physiological actions of the endogenous steroidal androgens testosterone
and dihydroxytestosterone (DHT). Several studies have demonstrated that androgens
increase bone mass and lean body mass but androgens also have associated adverse
effects such as hirsutism in women and prostate growth in men. Tissue Selective
Androgen Receptor Modulators (SARMs) are ligands of the androgen receptor that exert
AR agonism or antagonism with distinct tissue selectivity providing beneficial anabolic
actions on target tissues (bone or muscle) with minimal adverse effects on skin and
reproductive tissues. Scientists from Pfizer have developed an orally efficacious SARM,
MK-0773 that has anabolic action on muscle and bone with minimal androgenizing
effects. MK-0773 has been selected for development and is currently in Phase 2 clinical
trials for the treatment of Sarcopenia.
Identified from early medicinal chemistry efforts 4-Azasteroid 1 has demonstrated partial
agonism and to increase muscle mass and bone mass with similar efficacy to 0.1 mpk
DHT with little adverse effects on skin or uterus tissues in their in vivo model assay for
sarcopenia and osteoporosis. Starting from 4-Azasteroid 1, they have modified the Aring
and found that the potency was increased by the addition of fluoro substituent at the
2-position (Scheme 5).


They have also replaced the right-hand side aryl amide with an emphasis on increasing
the water solubility and improving the oral pharmacokinetic profile. Replacement of the
2-trifluoromethyl aryl amide with the azaimidazolyl amide resulted in azaimidazole MK-
0773. MK-0773 displaced excellent activity and selectivity in the in vitro assays and
possessed attractive pharmacokinetics parameters in dogs. It was selected for
development for the treatment of Sarcopenia.
In order to provide the enough material for phase 2 clinical trails, they have developed a
novel scalable route to prepare MK-0773. Scheme 6 delineated the synthesis of the lefthand
side 2-fluoro-4-azasreroid-17-carboxylic acid.


The Scheme 7 described the route for preparing the required azaimidazolyl amine and
completing the synthesis of MK-0773. They have prepared >150grams via this route.
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so what does ti do> SD? phera like?
 
already 2 Chinese suppliers if you look by CAS #

www dot lookchem dot com /cas-606/606101-58-0.html[/url]

someone should get some for research purposes and do HPLC
 
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