SARMs were first identified in 1998 as electrophilic derivatives of the anti-androgens bicalutamide and hydroxyflutamide. In 1999 analogs of quinolone-based AR antagonists were also reported to activate the AR.
Initially, bicalutamide analogs showed the most promise in vitro. In vivo the ability of these early bicalutamide-based compounds to activate the AR was limited, at best, by unfavorable pharmacokinetic properties. They were metabolized, and reduced to inactive metabolic products, before they could act as androgen receptor agonists. Moreover, some analogs were metabolized to active AR-antagonists, and exerted a negative effect on AR expression/function.
Upon analysis, the primary metabolic site was identified as the sulfur linkage off the B-aromatic ring. The B- ring itself was identified as the secondary metabolic site. The sulfur linkage could undergo successive oxidations to a sulfoxide and then to a largely-inactive sulfone. The B-aromatic ring could then be oxidized to a hydroxylated metabolite.
With the weak spots located, steps were taken to render them more resistant to metabolic breakdown. The sulfite in the linkage was changed to oxygen -- a change which had minimal effect on AR binding, while at the same time rendering the compound much more resistant to oxidation.
With that out of the way, research progressed on breakdown-resistant-bicalutamate-derivative SARMs. Dozens of compounds were analyzed, and it was found that AR binding is enhanced by:
-An electrophilic or electron-withdrawing substituent (cyano, nitro, fluoro, chloro) in the B-ring, para position (carbon 4).
-A nitro group in the A-ring, para position, increases in vitro binding affinity; a cyano (CN) group in the same position might not bind as strongly, but improves in vivo activity due to improved pharmokinetic properties. Both are common, though CN is now strongly preffered. In any case, options are limited, as there HAS to be a hydrogen-bond acceptor at this position for the compound to display any activity.
-A lipid-soluble group, typically CF3, on carbon 3 of the A-ring.
The B-ring deserves some more attention, as it is an important binding site, and substitutions here can have dramatic effects. (In some ways it's similar to the A-ring on the steroid skeleton.) AR <---> B-ring interaction is generally more favorable if:
-Cyano, acetamido (‒NHCOCH3), trifluoroacetamido, or chloroacetamido substituents are present at the para-position
-Binding affinity can be further increased if there are multiple electron withdrawing substitutions off ring-B... in which case, interaction is more favorable if:
---The molar mass of each substitution is low
---A H-bond acceptor (nitrogen or oxygen) is present at the 4- position of the B-ring
---If there are two electron-withdrawing groups, they are are at the 3-, and 4- positions of the B-ring
---If there are three electron-withdrawing groups, they are at the 2-, 4-, and 5-positions
Fluoro groups instead of chloro groups are incorporated in the B-ring for compounds with more than two substituents in that ring. The molecular weight of Cl is almost double that of F, and multiple chloro groups exert a negative effect on binding due to their bulk. In any case, even with only one substitution, B-ring F groups tend to produce a more favorable anabolic response than Cl groups.
Now that we are aware of the above, let's take a look at the bicalutamide-based SARMs which made it out of the lab.
Andarine (S-4)
Andarine is an S-isomer (hence the name S-4), with a nitro group (O2N) attached to C-4 of its A-ring, a trifluoromethyl group linked to the C-3, and a single attachment to the B-ring (para), which is an electron-withdrawing acetamido group.
S-23
Similarities: S-isomer, trifluoromethyl attached to the C-3 of the A-ring
Differences: Cyano group at C-4 of the A-ring, 2 attachments (F, Cl) to the B-ring,
Though the CN group reduces AR binding affinity, it makes the compound more effective in vivo. The 2 electron-withdrawing groups on the B-ring increase binding affinity, and also increase its anabolic effects. Chloro groups on the B-ring tend to be less selective and can strongly inhibit LH and FSH. S-23 is no exception to that observation -- it is, in fact, being researched for use as a male contraceptive due to its ability to inhibit spermatogenesis.
Mg for mg, S-23 may be more potent than S-4 or Ostarine. It is certainly more potent than the former due to the A-ring CN group modification which slows metabolism; it may be more potent than the latter due to the B-ring Cl and F groups, which strongly promote AR-binding.
Ostarine
Ostarine is identical to S-23, except at the B-ring, where the Cl and F groups are replaced by a single (para)Cyano group on carbon 4. As with the A-ring CN modification, I suspect that the 4-CN group here might improve pharmokinetic properties and display better in vivo activity, despite the fact that 3F,4Cl (or, likely even better, 3F,4F) should have better binding affinity.
S-4 and Ostarine are the only SARMs which, to my knowledge, are commercially available. If you are considering their use, it is worth keeping in mind that Ostarine was developed years after S-4, and by the same researchers -- though by then much wiser and more experienced! It is a more selective compound than S-4, it should display more anabolic effects due to a much longer half-life, and it should be metabolized more favorably due to the A-ring (para)cyano substitution. It is simply a much better compound... In fact, Ostarine is the best bicalutamide-based SARM that the researchers at GTx thought they could come up with, and it looks from here like there's no reason to doubt them.
...But there are other, even more powerful and selective SARMs on the horizon. Though they're nowhere near commercial availability, I'll write about them when I get the chance.
-Jake
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