# SARMs/ S4 anyone used this stuff



## besa (Jan 12, 2009)

*Nonsteroidal Selective Androgen Receptors Modulators*

*
(SARMs): Designer Androgens with Flexible Structures*

*
Provide Clinical Promise*
​
*
*



Androgens play an essential role in differentiation and

growth of the male reproductive tract, pubertal maturation

and development of secondary male sex characteristics, initiation

and regulation of spermatogenesis, and male sexual

behavior (1). Steroidal androgens increase muscle mass, bone

mass, and strength; stimulate male pattern baldness; and

alter serum lipid profiles and fat distribution (2). Testosterone

(T), synthesized and secreted by the testes, and its more

potent 5-reduced metabolite, dihydrotestosterone (DHT),

are the principal biologically active endogenous androgens.

T and DHT exert tissue-specific biological effects. For example,

T functions to stimulate muscle mass, sexual development,

and spermatogenesis, whereasDHTplays critical roles

in facial and body hair growth, acne, and prostatic enlargement.

The actions of both T and DHT are mediated by the

intracellular androgen receptor (AR), a member of the nuclear

receptor superfamily of ligand-activated transcription

factors (3, 4). Upon binding of T or DHT, AR undergoes a

conformational change, binds to specific DNA sequences

termed androgen response elements, forms complexes with

nuclear coregulatory factors, and modulates the transcription

of target genes. For decades, AR has been a target for

drug development focused upon the treatment of pathological

conditions arising from abnormal androgen levels or

altered target tissue responsiveness, the improvement of

physical performance, and the regulation of male fertility.

The primary focus for drug design has been the synthesis

of chemicals to regulate the transcriptional activity of AR

based upon the structural, steroidal or nonsteroidal, and

functional androgenic, antiandrogenic, or anabolic properties

of ligands. Steroidal androgens, represented by various

chemical derivatives of T, have been used clinically to treat

a variety of male and female disorders resulting from androgen

deficiency (5, 6). The principal clinical indication for

androgens is as replacement therapy in hypogonadal men.

Androgens have also been used clinically for the treatment

of delayed puberty in boys, anemia, primary osteoporosis,

hereditary angioneurotic edema, endometriosis, and muscle

diseases and wasting. More recently, androgens have been

used as hormone replacement therapy in aging men and for

regulation of male fertility. The use and abuse of androgens

as anabolic agents to enhance physical performance and endurance

has been highlighted recently among world-class

athletes participating in the Olympic games, as well as

among adolescents seeking athletic achievement. Antiandrogens

are used to counteract the undesirable actions of excessive

androgens to treat acne, hirsutism, and male pattern

baldness and to prevent androgen stimulation of prostatic

hyperplasia and carcinoma. Nonsteroidal antiandrogens

(Fig. 1), such as flutamide (Eulexin; Schering, Kenilworth,

NJ), nilutamide (Anandron; Aventis, Kansas City, MO), and

bicalutamide (Casodex; AstraZeneca, Wilmington, DE), are

referred to as pure antiandrogens because they bind exclusively

to AR and thus are devoid of antigonadotropic, antiestrogenic,

and progestational effects (7). These agents have

advantages over steroidal antiandrogens such as megesterol

acetate or cyproterone acetate in terms of specificity, selectivity,

and pharmacokinetic properties.

Whereas nonsteroidal antiandrogens have been used clinically

for many years, nonsteroidal androgens have only

recently been conceptualized. Better receptor selectivity of

nonsteroidal ligands has been achieved from the flexibility

by which structural modifications can be used to optimize

their physicochemical, pharmacokinetic, and pharmacological

properties. As recently demonstrated for the growing

class of selective estrogen receptor modulators (SERMs) that

includes tamoxifen and raloxifene, these nonsteroidal ligands

demonstrate tissue-selective actions and diverse activity

profiles that serve specific therapeutic needs (8). In this

issue of Endocrinology, Gao et al. (9) report on their continuing

progress toward the synthesis, development, and evaluation

of nonsteroidal selective androgen receptor modulators

(SARMs). Interestingly, this group of investigators has discovered

a series of novel derivatives of the nonsteroidal

antiandrogens, hydroxyflutamide and bicalutamide, that act

as nonsteroidal androgens (10 -13). These efforts complement

previous reports by other groups describing 2-quinoline,

coumarin, and phthalimide analogs that can be converted

to AR antagonists or agonists (14 -17). These

nonsteroidal compounds mark the emergence of a novel

category of pharmacological agents with potential applications

in androgen therapy. The discovery of nonsteroidal

androgens not only provides an opportunity to identify

agents with superior therapeutic index and pharmacokinetic

profiles compared with steroidal androgens but also presents

the reality that tissue-selective ARMs can be effectively developed

(18, 19).

The current report by Gao et al. (9) describes the tissue selectivity

in intact male rats of two SARMs, designated S1 and

S4, that behave as partial agonists in androgen-responsive tissues,

such as prostate and seminal vesicles, but full agonists in

anabolic tissues such as the levator ani muscle (12). Both S1 and

S4 bind with high affinity to AR, with dissociation constant of

the ligand inhibitor-receptor complex (Ki) values of 6.1 and 4.0
​


Abbreviations: AR, Androgen receptor; DHT, dihydrotestosterone;

Ki, dissociation constant of the ligand inhibitor-receptor complex;

SARM, selective androgen receptor modulator; T, testosterone.
​


*Endocrinology **is published monthly by The Endocrine Society (http://*

*
**www.endo-society.org**), the foremost professional society serving the*

*
endocrine community.*
​
*
*



0013-7227/04/$15.00/0 Endocrinology 145(12):5417-5419
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Printed in U.S.A. Copyright © 2004 by The Endocrine Society

doi: 10.1210/en.2004-1207
​


5417
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nm, respectively; which is similar to T, much higher than hydroxyflutamide

(Ki 25 nm), but lower than DHT (Ki 0.2

nm). In immature castrated rats, S1 and S4 exhibited full AR

agonist activity in levator ani muscle but only partial agonist

activity in prostate and seminal vesicles. The relative rates of

efficacy of S1 and S4 in prostate were 12 and 29%, respectively,

compared with T propionate. As reported by Gao et al. (9) for

intact male rats, S1 selectively decreased prostate weight with

efficacy similar to that of the 5-reductase inhibitor finasteride

without affecting the levator ani muscle or altering the plasma

levels of T, LH, or FSH. By contrast, hydroxyflutamide decreased

both the prostate and levator ani muscle weights without

selectivity and increased plasma hormone levels in a dosedependent

fashion. Neither S1 nor S4 affected 5-reductase

type I or II isozyme activities. These results show that S1 and

S4 act as partial AR agonists with tissue-selective activity that

suppresses androgen-dependent prostate growth without influencing

the anabolic effects of T on weight of the levator ani

muscle. Moreover, the maintenance of normal serum T levels

and lack of effect of S1 and S4 on pituitary gonadotropin secretion

further exemplify the tissue selectivity of their action.

The derivation of S1 and S4 is based on earlier studies by

this group of investigators that focused upon key structural

elements previously determined to be important for AR

binding of nonsteroidal ligands, such as bicalutamide and

hydroxyflutamide (20, 21). In their evaluation of structureactivity

relationships for nonsteroidal ligands, AR binding

affinity of bicalutamide derivatives was enhanced in the

R-isomers defined by the sulfur linkage to the meta-carbon

in the aromatic B-ring, by an electrophilic para-substituent in

the aromatic B-ring, by a nitro group in the para-position of

the A-ring, and by a trifluoromethyl group linked to the

chiral carbon (11). They discovered, however, that hepatic

oxidation of the sulfur linkage led to rapid in vivo inactivation

and reduced efficacy of several bicalutamide derivatives (22).

To block oxidation, the thio linkage was modified to an ether

linkage, creating the S-isomers, and a fluoride (S1), propionate

(S3), or acetamido group (S4) was placed in the paraposition

of the B-ring (Fig. 2). This group of compounds

demonstrated high in vitro AR binding affinity and efficacy

in assays of AR-mediated reporter gene activity, but only S1

and S4 exerted in vivo androgenicity (increased prostate and

seminal vesicle weights) and anabolic activity (increased levator

ani muscle weight) in castrated immature rats (12). In

the context of these findings, it is important to point out that
​


in vitro binding affinity cannot distinguish agonist or antagonist

activity. Moreover, observation of in vitro agonist activity

of a compound in transfection assays does not always

predict in vivo efficacy that is additionally influenced by

route of administration, disposition, and metabolism.

A likely explanation as to how these synthetic ligands act

as agonists or antagonists is related to their ability to induce

specific conformational changes in AR (23, 24). The AR ligand

binding domain is composed of 12 -helices. In the

crystal structure, relatively few amino acid residues were

found to interact directly with the steroidal agonists, DHT

and methyltrienolone (R1881) (25, 26). Most of these residues

are hydrophobic in nature and interact with hydrophobic

moieties in the ligand, whereas fewer residues are hydrophilic

and may form hydrogen bonds with polar atoms in the

ligand. In the case of nonsteroidal ligands, AR binding is

likely to be influenced by stereoisomeric conformation and

steric and electronic effects. It remains to be determined

whether the same amino acids in the ligand binding pocket

interact with both steroidal and nonsteroidal ligands. As

evidenced by structure-function studies of nonsteroidal ligands,

minor differences in ligand structure can lead to either

agonist or antagonist activity (11). The AR can use different

transactivation domains, AF-1 and AF-5 in the amino-terminal

domain and AF-2 in the carboxy-terminal domain

(27-30). The AF-2 function is strongly dependent upon interaction

with nuclear receptor coactivators, whereas strong

agonist, but not antagonist, binding induces ligand-dependent

interaction internally between the AF-2 and AF-1 domains

(31-33). When steroid agonists bind to AR, helix 12

containing the AF-2 region in the ligand binding domain

closes over the binding pocket revealing an interface for

coactivator interaction. Conversely, binding of antagonists

maintains helix 12 in an open conformation directed away

from the binding pocket. Therefore, tissue selectivity of nonsteroidal

androgen action may depend upon ligand-induced

AR conformation and recruitment of a tissue-specific repertoire

of coregulatory factors that function as coactivators or

corepressors.

In summary, the novel features of designer androgens may

find application in numerous medical situations. The potent

androgenic/anabolic effects on muscle, bone, and mental

function may improve the quality of life for those with

chronic diseases or for aging men if the potential adverse

effects on the cardiovascular system and the prostate can be

divorced. Although the factors that determine tissue selectivity

of androgen action remain to be explored, the current

report by Gao et al. (9) confirms the critical nature that ligand
​


FIG. 1. Structures of nonsteroidal antiandrogens.

FIG. 2. Chemical modifications to the nonsteroidal backbone of the

antiandrogen bicalutamide (Fig. 1) were used to create SARMs with

agonist activity in which R1OH, XO, and R2 in the para-position

of the B-ring was F (S1), COC2H5 (S3), or NHCOCH3 (S4).
​


*5418 *Endocrinology, December 2004, 145(12):5417-5419 Brown • News & Views
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structure plays in regulating AR function in different tissues.

The flexibility in design of nonsteroidal AR ligands provides

the opportunity to exploit the beneficial effects of androgens

while ameliorating their undesirable effects.

Terry R. Brown

Department of Biochemistry and Molecular Biology

Johns Hopkins Bloomberg School of Public Health

Baltimore, Maryland 21205
​


*Acknowledgments*
​
*
*



Received September 10, 2004. Accepted September 15, 2004.

Address all correspondence and requests for reprints to: Terry R.

Brown, Ph.D., Department of Biochemistry and Molecular Biology,

Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe

Street, Baltimore, Maryland 21205. E-mail: [email protected]
​


*References*
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*
*



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*Endocrinology **is published monthly by The Endocrine Society (*

*http://www.endo-society.org**), the foremost professional society serving the*

*
endocrine community.*
​
*
*



Brown • News & Views Endocrinology, December 2004, 145(12):5417-5419 *5419*
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*
*Downloaded


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## besa (Jan 12, 2009)

Was bored at work as normal and was surfing the net and came across this.

Any more info would be gr8.

Thanks


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## besa (Jan 12, 2009)

This is off another forum.

Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats.

* Gao W,

* Reiser PJ,

* Coss CC,

* Phelps MA,

* Kearbey JD,

* Miller DD,

* Dalton JT.

Division of Pharmaceutics, College of Pharmacy and Department of Oral Biology, The Ohio State University, 500 West 12th Avenue, L. M. Parks Hall, Room 242, Columbus, Ohio 43210, USA.

The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights more than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.

Ah yes, SARM. Basically a classification of syndrogens, that by defenition, exert the ability to bind with the androgen receptor. It is a broad class of products, that is totally unrelated to AAS. Their tendency to bind to the androgen receptor, means there will be no actual androgenic side-effects in the body.

The study that you speak of is a rat study done on 4 SARM. Two of them, S2 and S3, showed binding to the androgen receptor, but no anabolic activity. The other two, S1 and S4 (see full name above), did show anabolic activity, with one of them (S4 I believe) having a higher anabolic effect than test prop.

Some SARM work orally, some are injectible.

I'm currently not experimenting with them, but I am keeping my eye on them. The medical community is experimenting with acetothiolutamide, and human trials with ostarine and andarine have already been done. Still pretty experimental so far, but they are considered a possible replacement to steroids in the medical community

So where does that leave SARM for the BB?

*SARM that inhibit androgenic sides, and are anabolic, can be taken by itself;

or

*SARM that inhibit androgenic sides, but are NOT anabolic, can be taken along with steroids. The result will be no change in anabolic activity (tests have already been done on that), and an inhibition of androgenic sides.

So how to get them? Well, the medical community is still experimenting. But that doesn't stop the supplement industry. One product exists as SARM-X. Active ingredient is Trans-4-Hydroxy-3-Methoxycinnamic Acid.

"SARM-X is the first of a new class of designer androgenic / anabolic steroid memetic compounds; the most advanced legal over-the-counter compound available anywhere!"

Yeah. Well, on the positive side, it is in fact a SARM. On the negative side, this supplement uses a fancy name for ferulic acid, a phenol found i.e. in grains, oatmeal and brown rice. An interesting compound, but one of the SARM with zero anabolic activity. Still useful to counter androgenic sides though. Studies on that specific SARM have been done with success on deca and test, both with the SARM attached to the androgenic hormone, or taken separately


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## besa (Jan 12, 2009)

come on some1 has to have tried it.any feed back would be great.


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## Mars (Aug 25, 2007)

Look on AR, there's one guy who says he tried it in PCT.


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## TVRTUSCAN (Nov 5, 2008)

I just got a 5 capsules of RPM from Applied Neutriceuticals when i ordered from BB Warehouse.

No idea what they are but it says they are a SARM.

Way to read up on them before trying them out.


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## thevoice (May 10, 2007)

IMO this will be used in a lot of cycles by nealry everyone, quite a few have tried it in the states and report big strength increases, muscle gain (although not to the level or a typical cycle), good feeling on it etc the best benfit though its proving to not have any effect on natrual levels and some have used it in PCT to help keep there gains while natrual levels come back online.

Its meant to be as potent as testsostrone anabolic wise. As soon as the underground labs start churning this out i think a lot of people will use it along side steroids or even stand alone. Also it it proves to be safe which it looks to be so far it will be hard for any govenerments to try and outlaw it.


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