SARMs - The Future of Bodybuilding?!

[AleX-69]

Hi guys,

i noticed there was no information on these boards about SARMs [Selective Androgen Receptor Modulators]. So i decieded to sum up what I know about the topic and hope that some of you will chime in, so that we can get a little more info on that topic.

A SARM is a substance which excerts a primary anabloic effect and only a very weak androgenic effect. In some cases it even has an AR-Agonist behavior.
The first SARM was discovered in 1998. Scientist could observe a high affinity for the androgen receptor in this compound (10 times higher than testosterone and equal to DHT).
Based on these findings research continued and finally the first REAL SARM was discoverd. SARMs are tissue selective and exert its effects mostly in anabolic tissue (i.e. muscle) whereas androgenic tissue (i.e. prostate) is affected only to a minor extend. Moreover several SARM also have a positive impact on bone densitiy and cartilage not unlike deca .
The first developed SARM (S-1) was 3-(4-Fluorophenoxy)-2-Hydroxy-2-Methyl-N-[4-Nitro-3-5 (Tr***uoromethyl)Phenyl]-Propanamid. (see structure in attachment)

S-1 could maintain bodyweight and muscle mass in castrated rats whereas only a minor increase in prostate weight was observed. Moreover S-1 even blocks the androgenic activity of testosterone in androgenic tissue by taking up its receptors but not activating them. Newer SARMS like S-1; S-2; S-3 and S-4 have varrying degrees of androgenic activity (3-15%) in comparsion to DHT but a 100% anabolic activity.

Moreover it is interesting to now that S-1 and S-4 do not cause significant LH suppression at all while maintaing the anabolic activity of Tesosterone Propionate .



Pharmacodynamics of Selective Androgen Receptor Modulators (SARMs)
Donghua Yin 1, Wenqing Gao 1, Jeffrey D. Kearbey 1, Huiping Xu 1, Kiwon Chung 2, Yali He 2, Craig A. Marhefka 2, Karen A. Veverka 3, Duane D. Miller 2, James T. Dalton 1*

1 The Ohio State University 2 The University of Tennessee 3 GTx, Inc.

* Address correspondence to: E-mail: [email protected]

Abstract

The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacologic activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with Ki values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacologic activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, while levator ani muscle weight was used as a measure of anabolic activity. The maximal response (Emax) and dose for half-maximal effect (ED50) were determined for each compound and compared to that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant LH or FSH suppression at doses near the ED50. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.

Selective Androgen Receptor Modulator (SARM) Treatment Improves Muscle Strength and Body Composition, and Prevents Bone Loss in Orchidectomized Rats
Wenqing Gao, Peter J. Reiser, Christopher C. Coss, Mitch A. Phelps, Jeffrey D. Kearbey, Duane D. Miller, and James T. Dalton*
Division of Pharmaceutics, College of Pharmacy, ***artment of Oral Biology, College of Dentistry, The Ohio State University, Columbus, OH 43210; ***artment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163

* To whom correspondence should be addressed. E-mail: [email protected].


The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in our previous study (Endocrinology 145(12):5420-28, 2004). In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-tr***uoromethyl-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 weeks. 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 (3 mg/kg) treated animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights over 2-fold greater than that observed in intact controls, while S-4 (3 mg/kg) returned these androgenic organs to only 16% and 17%, respectively, of the control levels. S-4 (3, 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 (BMD) 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 ***endent 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.

[AleX-69]

Some interesting Charts from an upcoming SARM researched by Orion Corp. Sadly this product is only in Clinical Phase II which implys that we would have to wait at least 6-8 years for it to hit the market.

[Property of Steroid.com]

Actually, I have been researching SARMs for years. I think they may be the future of PED use...I even contacted a research chem company to see if they wanted to produce them (provided them with tons of research), but they thought that it would be too flagrant and they didn't go through with it.

The one we were looking to produce was as anabolic as test but with 0 shutdown.

[AleX-69]

Actually, I have been researching SARMs for years. I think they may be the future of PED use...I even contacted a research chem company to see if they wanted to produce them (provided them with tons of research), but they thought that it would be too flagrant and they didn't go through with it.

The one we were looking to produce was as anabolic as test but with 0 shutdown.

I really hope you will have success in this matter, some time in the future..
I believe you could sell so much of this stuff its not even funny

[plzr8]

wow really interesting stuff....gonna try to dig up some more info online

[Property of Steroid.com]

I really hope you will have success in this matter, some time in the future..
I believe you could sell so much of this stuff its not even funny

I wasn't going to sell it. I just work with a chem company who I thought may want to sell it. I wasn't even asking for a %.

I don't think they had success sourcing it, though, in any case.

I remember some very interesting peptides that I've used that never made it to the general market (EPOrP, etc...)...there's just too many cost prohibitive factors with many.

[314159265358]

Actually, I have been researching SARMs for years. I think they may be the future of PED use...I even contacted a research chem company to see if they wanted to produce them (provided them with tons of research), but they thought that it would be too flagrant and they didn't go through with it.

The one we were looking to produce was as anabolic as test but with 0 shutdown.

Outside of the fact that no large scale side-effects profiles have been done, I think SARMs represent the clear choice intellectually for anabolic compounds. Considering this field is in its infancy, its amazing compounds with these profiles have been discovered.

From some other sites, it seems that at least some of these compounds are currerntly VERY expensive to produce.

I've been trying to get the information on those SARMs that have peer reviewed data and which of those (and their alternate names) are in clinical trials.

Some examples:

(1) the S-1; S-2; S-3 and S-4 compounds of Dalton's group mentioned above

(2) GTx, Inc.

(A) ostarine: http://www.gtxinc.com/tech/ostarine.htm

Ostarine, a SARM, is being developed to treat a variety of medical conditions relating to muscle wasting and/or bone loss in acute and chronic diseases. Ostarine is a novel non-steroidal agent designed to have anabolic activity like testosterone without unwanted side effects on the prostate and skin and in a once daily oral dose. GTx initiated a proof of concept Phase II clinical trial of ostarine in May 2006 and completed enrollment in July 2006. The three month placebo controlled clinical trial is evaluating multiple doses of ostarine in 60 elderly men and 60 postmenopausal women. The trial is designed to evaluate the activity of ostarine on building muscle and promoting bone as well as to assess safety in both elderly men and postmenopausal women. Endpoints of the trial include measurements of bone, fat, and muscle. GTx expects to report the data from the Phase II clinical trial in the fourth quarter of 2006. Based on ostarine’s Phase II clinical data profile, GTx will select specific acute and chronic muscle wasting and/or bone loss diseases for further development. GTx plans to initiate a Phase IIb or Phase III clinical trial of ostarine in 2007.

trial info: http://phx.corporate-ir.net/phoenix....0363&highlight

(B) andarine (in partnership with J&J I think)
http://www.bizjournals.com/memphis/s...07/story1.html

Couldn't find much out here except for trials that were to begin as few years ago. Unless I missed some positive report, that's likely a bad sign!

(3) S-40503 from Central Research Laboratories, Kaken Pharmaceutical Co.

Biol Pharm Bull. 2003 Nov;26(11):1563-9. Links

Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis.

Hanada K, Furuya K, Yamamoto N, Nejishima H, Ichikawa K, Nakamura T, Miyakawa M, Amano S, Sumita Y, Oguro N.

Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Shinomiya, Kyoto, Japan. [email protected]
A novel nonsteroidal androgen receptor (AR) binder, S-40503, was successfully generated in order to develop selective androgen receptor modulators (SARMs). We evaluated the binding specificity for nuclear receptors (NRs) and osteoanabolic activities of S-40503 in comparison with a natural nonaromatizable steroid , 5alpha-dihydrotestosterone (DHT). The compound preferentially bound to AR with nanomolar affinity among NRs. When S-40503 was administrated into orchiectomized (ORX) rats for 4 weeks, bone mineral density (BMD) of femur and muscle weight of levator ani were increased as markedly as DHT, but prostate weight was not elevated over the normal at any doses tested. In contrast, DHT administration caused about 1.5-fold increase in prostate weight. The reduced virilizing activity was clearly evident from the result that 4-week treatment of normal rats with S-40503 showed no enlargement of prostate. To confirm the bone anabolic effect, S-40503 was given to ovariectomized (OVX) rats for 2 months. The compound significantly increased the BMD and biomechanical strength of femoral cortical bone, whereas estrogen, anti-bone resorptive hormone, did not. The increase in periosteal mineral apposition rate (MAR) of the femur revealed direct bone formation activity of S-40503. It was unlikely that the osteoanabolic effect of the compound was attribute to the enhancement of muscle mass, because immobilized ORX rats treated with S-40503 showed a marked increase in BMD of tibial cortical bone without any actions on the surrounding muscle tissue. Collectively, our novel compound served as a prototype for SARMs, which had unique tissue selectivity with high potency for bone formation and lower impact upon sex accessory tissues.

(4) LGD2226 of Ligand Pharmaceuticals

J Musculoskelet Neuronal Interact. 2002 Mar;2(3):222-4.Links
Novel, non-steroidal, selective androgen receptor modulators (SARMs) with anabolic activity in bone and muscle and improved safety profile.

Rosen J, Negro-Vilar A.
Ligand Pharmaceuticals, San Diego, CA 92121, USA.
A novel approach to the treatment of osteoporosis in men, and possibly women, is the development of selective androgen receptor modulators (SARMs) that can stimulate formation of new bone with substantially diminished proliferative activity in the prostate, as well as reduced virilizing activity in women. Over the last several years, we have developed a program to discover and develop novel, non-steroidal, orally-active selective androgen receptor modulators (SARMs) that provide improved therapeutic benefits and reduce risk and side effects. In recent studies, we have used a skeletally mature orchiectomized (ORX) male rat as an animal model of male hypogonadism for assessing the efficacy of LGD2226, a nonsteroidal, non-aromatizable, and non-5alpha-reducible SARM. We assessed the activity of LGD2226 on bone turnover, bone mass and bone strength, and also evaluated the effects exerted on classic androgen-dependent targets, such as prostate, seminal vesicles and muscle. A substantial loss of bone density was observed in ORX animals, and this loss was prevented by SARMs, as well as standard androgens. Biochemical markers of bone turnover revealed an early increase of bone resorption in androgen-deficient rats that was repressed in ORX animals treated with the oral SARM, LGD2226, during a 4-month treatment period. Differences in architectural properties and bone strength were detected by histomorphometric and mechanical analyses, demonstrating beneficial effects of LGD2226 on bone quality in androgen-deficient rats. Histomorphometric analysis of cortical bone revealed distinct anabolic activity of LGD2226 in periosteal bone. LGD2226 was able to prevent bone loss and maintain bone quality in ORX rats by stimulating bone formation, while also inhibiting bone turnover. LGD2226 also exerted anabolic activity on the levator ani muscle. Taken together, these results suggest that orally-active, non-steroidal SARMs may be useful therapeutics for both muscle and bone in elderly hypogonadal men through their anabolic activities. Since SARMs both prevent bone loss, and also stimulate formation of new bone, they may have significant advantages relative to currently used anti-resorptive therapies. Coupled with their activity in muscle and their ability to maintain or restore libido, they offer new therapeutic approaches for male and female hormone replacement.

Endocrinology. 2007 Jan;148(1):363-73. Epub 2006 Oct 5. Links
An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate.

Miner JN, Chang W, Chapman MS, Finn PD, Hong MH, López FJ, Marschke KB, Rosen J, Schrader W, Turner R, van Oeveren A, Viveros H, Zhi L, Negro-Vilar A.
Research Development, Ligand Pharmaceuticals Inc., San Deigo, California 92121, USA. [email protected]
A number of conditions, including osteoporosis, frailty, and sexual dysfunction in both men and women have been improved using androgens. However, androgens are not widely used for these indications because of the side effects associated with these drugs. We describe an androgen receptor (AR) ligand that maintains expected anabolic activities with substantially diminished activity in the prostate. LGD2226 is a nonsteroidal, nonaromatizable, highly selective ligand for the AR, exhibiting virtually no affinity for the other intracellular receptors. We determined that AR bound to LGD2226 exhibits a unique pattern of protein-protein interactions compared with testosterone, fluoxymesterone (an orally available steroidal androgen), and other steroids , suggesting that LGD2226 alters the conformation of the ligand-binding domain. We demonstrated that LGD2226 is fully active in cell-based models of bone and muscle. LGD2226 exhibited anabolic activity on muscle and bone with reduced impact on prostate growth in rodent models. Biomechanical testing of bones from animals treated with LGD2226 showed strong enhancement of bone strength above sham levels. LGD2226 was also efficacious in a sex-behavior model in male rats measuring mounts, intromissions, ejaculations, and copulation efficiency. These results with an orally available, nonaromatizable androgen demonstrate the important role of the AR and androgens in mediating a number of beneficial effects in bone, muscle, and sexual function independent from the conversion of androgens into estrogenic ligands. Taken together, these results suggest that orally active, nonsteroidal selective androgen receptor modulators may be useful therapeutics for enhancing muscle, bone, and sexual function.


Although in "Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery" (nice review, btw), Dalton et al note that there are significant potential liver toxicity issues with this drug

(5) BMS-564929 of Bristol-Myers Squibb

Endocrinology. 2007 Jan;148(1):4-12. Epub 2006 Sep 28. Links
Comment in:
Endocrinology. 2007 Jan;148(1):1-3.
Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats.

Ostrowski J, Kuhns JE, Lupisella JA, Manfredi MC, Beehler BC, Krystek SR Jr, Bi Y, Sun C, Seethala R, Golla R, Sleph PG, Fura A, An Y, Kish KF, Sack JS, Mookhtiar KA, Grover GJ, Hamann LG.
Department of Metabolic Diseases, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.

(6) 10c and a bunch of others from Johnson and Johnson Pharmaceutical Research

Serendipitous discovery of novel imidazolopyrazole scaffold as selective androgen receptor modulators

Xuqing Zhang, a, , Xiaojie Lia, George F. Allana, Tifanie Sbrisciaa, Olivia Lintona, Scott G. Lundeena and Zhihua Suia
aDrug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA
Received 24 August 2006; revised 10 October 2006; accepted 12 October 2006. Available online 17 October 2006.

http://www.sciencedirect.com/science...390cb6b0b2cd97


http://www.sciencedirect.com/science...f53154525f9924

there are more on discovery and chemical modifications - the field is exploding

[Anavar Man]

I was just re-reading an article on this in march 2006 Muscular Development, intersesting stuff, i wish it would hit the market sooner.

[Amorphic]

Totally fascinating read, this could definetly be something huge 10 years for now, SARM's and myostatin blockers=absolutely crazy stuff. For now its just something to imagine.