SARMs – History and Development

SARMs or selective androgen receptor modulators are the latest in receptor agonists currently in develpoment.

There are many different compounds being developed, analysed and tested including the Bicalutamide based analogs, Quinolinone-based SARMs and Hydantoin derivative SARMs.

The current commercially available SARMs S4 and Ostarine are both Bicalutamide based and this article will shed light onto their development.

I.D of SARMs

The identification of SARMs first occured in the late 1990s as electrophilic derivatives of the anti-androgens bicalutamide and hydroxyflutamide.

bicu

During this period, analogs of quinolone-based androgen receptor antagonists were also reported to activate the androgen receptor. The analogs of bicalutamide showed the most promise in vitro (non-living). However in vivo (living organisms), the ability of bicalutamide analogs on androgen receptor activation was limited by unfavorable pharmacokinetic properties. In vivo, the bicalutamide analogs were metabolized, and reduced to inactive metabolic products before they could activate the androgen receptor. Also some analogs were even metabolized to active androgen receptor-antagonists, therefore exerting an opposite effect to the intention of androgen recpetor activation.

The primary metabolite was was identified as the sulfur linkage off the B-aromatic ring. Whereas the B ring was identified as the secondary metabolic site. The sulfur linkage could undergo successive oxidations to a sulfoxide and then to a mostly inactive sulfone. The B-aromatic ring could then be oxidized to a hydroxylated metabolite. Once these metabolites were identified, the appropriate actions could take place to give a greater resistance to metabolic breakdown. To have minimal effect on androgen receptor binding abilities, the linkage sulfite was changed to oxygen which made the compund much more resistant to oxidation. Research then progressed onto bicalutamate-derivative SARMs that were resistant to breakdown

Several different compounds were investigated and analyzed which revelaed that androgen receptor binding was enhanced by:

-An electrophilic or electron-withdrawing substituent (cyano, nitro, fluoro, chloro) in the B-ring, para position (carbon 4).

-A lipid-soluble group, typically CF3, on carbon 3 of the A-ring.

There must also be a hydrogen-bond acceptor at the A ring position for the compound to display any activity.

-A nitro group in the A-ring para position, increases in vitro binding affinity;

-A cyano (CN) group in the A-ring para position, also increases in vitro binding affinity.

Both A ring occupations are common, though the cyano group has now become the preference.

The B-ring is also an important binding site, and molecule substitutions here can have very prominant effects. B-ring to androgen receptor 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 of the B-Ring.. So when:

-The molar mass of each substitution is low

-When there are 3 e- withdrawing groups, the three groups are at the 2-, 4-, and 5-positions of the B-ring

-When there are 2 e- withdrawing groups, the two groups are at the 3-, and 4-positions of the B-ring

-A H-bond acceptor (nitrogen or oxygen) is present at the 4- position of the B-ring

-Fluoro groups instead of chloro groups are incorporated in the B-ring for compounds with more than two substituents in that ring (due to molar weight issues).

From the above points, the following bicalutamide-based SARMs were synthesized:

Andarine (S-4)

Andarine is an S-isomer (hence the name S-4), with a nitro group (O2N) attached to C-4 of the 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.

512px_Andarine

S-23

Similar to S4, S-23 is an S-isomer with a trifluoromethyl droup attached to the C-3 of the A-ring. However unlike S4, S-23 has a cyano group at C-4 of the A-ring and 2 attachments (F, Cl) to the B-ring.

Although the cyano group reduces in vitro AR binding affinity, the effectiveness in vivo is greater. The 2 electron-withdrawing groups on the B-ring increase binding affinity, and also increase its anabolic effects. However the chloro groups on the B-ring tend to be less selective to only muscle tissue and can strongly inhibit LH and FSH causing greater suppresion of endogenous testosterone levels. Due to this, S-23 is no longer being viewed as a SARM in the general sense, but is being researched for use as a male contraceptive due to its FSH inhibition and therfore its ability to inhibit spermatogenesis.

S_23

Ostarine

Ostarine is again similar to S4 and identical to S-23, apart from at the B-ring where the Cl and F groups are replaced by a single (para) cyano group on C-4. As with the A-ring CN modification, the 4-CN group here may improve pharmokinetic properties and display better in vivo activity, despite the fact that 3F or 4Cl should have better binding affinity.

240px_Ostarine

S-4 and Ostarine are the only SARMs which are currently 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 At GTx. Ostarine is a more selective compound than S4, and displays more anabolic effects due to 24 hour half-life compared to the 4 hour half life of S4. Ostarine should also be metabolized more favorably due to the A-ring (para) cyano substitution. Hence Ostarine is the best bicalutamide-based SARM that the researchers at GTx have developed.

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