Tuesday, January 4, 2011

Hydantoin Derivative SARMs: BMS-564929

Hydantoin derivatives are another interesting class of anabolic SARMs, and like all of the others, they were first identified as analogs of non-steroidal anti-androgens... In this category, the most noteworthy anabolic SARM is BMS-564929, which was identified as an analog of the anti-androgens BMS-434681, BMS-15, and several others from that family. 

((7R,7aS)-2-Chloro-4-(7-hydroxy-1,3-dioxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile)

BMS-564929's binding action is quite well understood. It interacts with the androgen receptor via its CN group and its hydroxyl group. The CN group interacts with the AR at precisely the same position as DHT's 3-keto group, and the hydroxyl group occupies roughly the same position as DHT's 17ß-hydroxyl group. But BMS-564929 has another interesting, and quite unique, trait: It's phenyl ring directly and strongly interacts with the androgen receptor, and can induce conformational changes in the ligand binding domain unlike those seen with steroids -- which, as a rule, do not interact with the AR in such a manner. It also has an extremely strong affinity for the AR, with an in vitro Ki value of 2.11(nm). S-4, the Bicalutamide-based SARM with the greatest in vitro binding affinity (but, alas, a very poor pharmacokinetic profile!), has an inferior Ki value of 4.0. BMS-564929 has virtually no affinity for the ER or PR.

It's metabolic profile is also quite impressive. It is orally bioavailable, is completely resistant to reduction via 5α-reductase and aromatase, and has absolutely no detectable affinity for SHBG. Though data on its half-life has not been released, we can assume that it is highly favorable, as BMS-564929 was only administered once a day in animal studies. (Oral administration.)

As far as anabolic potency is concerned, it was shown to display an ED50 of 0.0009 mg/kg in the levator ani and an ED50 of 0.14 mg/kg in the prostate. In the same study, Testosterone Propionate exhibited an ED50 of 0.21 mg/kg in the levator ani and an ED50 of 0.42 mg/kg in the prostate, We can therefore assess BMS-564929's anabolic/androgenic activity to be roughly 23000/250, with a resultant Q ratio of ~90. With that said, an effective dose at restoring muscle mass (to 100%, or baseline,) in castrated rats was shown to be 0.1mg/kg. A tenfold larger dose -- 1mg/kg -- was only slightly more effective. There is clearly a point of diminishing returns.

Unlike some other SARMs, BMS-564929 is a powerful LH suppressant. It is 33 times more potent at LH suppression than Testosterone. The implications of this are that this is absolutely not a SARM to be taken with PCT -- this a SARM that in itself will require a very dialed-in PCT after use... 

...If anybody is ever going to use it, that is... See, for reasons not entirely clear, BMS-564929 was dropped by Bristol Myers Squibb. They sold the rights to their SARM program to Pharmacopeia Drug Discovery -- a company which itself was recently bought by Ligand Pharmaceuticals. Ligand is apparently pushing an unidentified SARM (very probably BMS-564929) through Phase I studies -- but it seems unlikely that they have the financial clout to bring it to market on their own. It is one of the only drugs in Ligand's pipeline which they are developing without assistance from a larger pharmaceutical company, and the smart money says it's doomed unless they find a partner for it fast
BMS-564929 is also not commercially available via the usual 'research chemical' channels, and may never be, because it is remarkably difficult to synthesize. Allow me to stress this point: This SARM is extremely difficult to make... And if a chemical manufacturer ever bothers to try its hand at producing a batch, it'll probably be one of the more expensive specialty chemicals on the market. (It could realistically cost hundreds or thousands per gram.)

In theory, active analogs are very easy to come up with. Don't touch the structural elements, the hydroxyl group or the cyano group -- simply replace the Cl group with a F or Br group. And there you have it: A different compound, but probably just as active as BMS-564929. One could do more -- for example, the keto groups don't interact with the AR, and can be modified without a reduction in activity -- but why bother? Not like anybody's going to make it...

I will write a bit about quercetin-based SARMs when I get the opportunity.

-Jake