SARMS: The Future?
- 10-09-2006, 01:22 AM
SARMS: The Future?
I've been keeping one eye on the development of SARMS (Selective Androgen Receptor Modulator). It appears many of the labs are able to pin point exactly what receptors to bind to, which avoids many problems associated with regular TRT. So, you can design a SARM that has anabolic, libidio enhancing characteristics that will not effect hair loss (or may even grow hair), will not convert to estrogen, will not damage liver function, blood pressure or lipids. Also, it is ORALLY available.
here is a recent abstract:
Endocrinology. 2006 Oct 5; [Epub ahead of print] 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,
* Lopez FJ,
* Marschke KB,
* Rosen J,
* Schrader W,
* Turner R,
* van Oeveren A,
* Viveros H,
* Zhi L,
* Negro-Vilar A.
Research and Development, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121; NIEHS/NIH - Environmental Diseases & Medicine Program, Research Triangle Park, NC; Metabasis Therapeutics, Inc. 11119 North Torrey Pines Rd., La Jolla, CA 92037; Department of Nutrition and Exercise Sciences, Oregon State University, 127 Milam Hall, Corvallis, OR 97331.
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 ligand that maintains expected anabolic activities with substantially diminished activity in the prostate. LGD2226 is a non-steroidal, non-aromatizable, highly selective ligand for the androgen receptor (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 (LBD). 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, non-aromatizable androgen demonstrate the important role of the androgen receptor 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, non-steroidal SARMs may be useful therapeutics for enhancing muscle, bone and sexual function.
PMID: 17023534 [PubMed - as supplied by publisher]
- 10-09-2006, 09:35 AM
10-09-2006, 12:10 PM
10-09-2006, 12:15 PM
10-10-2006, 12:39 PM
10-10-2006, 12:59 PM
10-10-2006, 01:30 PM
Here's how you make it... And look at GTXI
I believe GTx, Inc. "The Men's Health Biotech Company." ticker: GTXI owns this patent. They also make FARESTON (which may be familiar to some of you) and ACAPODENE. I own the stock and it's been doing well.The present invention relates to a synthetic process for the preparation of a novel class of androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen relacement and/or other clinical therpauetic and/or diagnostic areas. The process of the present invention is suitable for large-scale preparation, since all of the steps give rise to highly pure compounds, thus avoiding complicated purification procedures which ultimately lower the yield. Thus the present invention provides methods for the synthesis of non-steroidal agonist compounds, that can be used for industrial large-scale synthesis, and that provide highly pure products in high yield.
OSTARINE will be the name of the muscle-wasting SARM.
10-10-2006, 01:33 PM
10-10-2006, 02:10 PM
Do you know why GTx is limiting the application of ostarine to "muscle wasting" and treatment of sarcopenia in aging males? You would think that treat of hypogonadism/andropause would have a larger market.
Originally Posted by blackheart
10-10-2006, 02:22 PM
I wouldn't rule additional applications of this drug out (Another reason why I continue to like the stock). But if you breeze through the patent document, you'll see that they have included a large number of potential drugs within the scope of the patent, focused on various applications. It's possible that there's something better than OSTARINE in there, but I am not qualified to say. ACAPODENE is intended both for the Treatment for the side effects of Androgen Deprivation Therapy (I believe it may become to SERM of choice for athletes) and for Prevention of prostate cancer in men.Originally Posted by Random987
(for some reason i cannot post a linked image, but see the attached graphic)Selective Androgen Receptor Modulators (SARMs)
A selective androgen receptor modulator, or SARM, is a small molecule that binds to and selectively modulates androgen receptors depending on tissue type. In men, SARMs may be able to:
* Stimulate testosterone's beneficial action in bone, muscle and brain
* Block testosterone's harmful action in the prostate and skin
* Either cross or not cross into the central nervous system to affect lipids
Because of these properties, we believe SARMs could be developed to treat a range of medical conditions and physiological functions, including:
10-10-2006, 02:24 PM
10-10-2006, 02:27 PM
Yeah, it almost seems like they can make it a designer drug, you want muscle building, pro-sexual effects, hair gain, no aramotase, and orally available, come on down.
Might be hard to get past the FDA. Somewhat like the Melanotan battle, the drug that tans you, helps out sexual and may cause you to lose weight. They felt they needed to split it up to get approval. Too many effects.
Originally Posted by blackheart
10-10-2006, 03:28 PM
anything that can change the health of someone for the better in more ways than one will always be controlled. Why is that they keep things that can be good for us out of our hands? Its not like tylenol or any other OTC drug cant be abused...They just make more profit from selling it with prescription only. But again we have to look at all the benefiets of this SARM and know that there has to be a gang of sides to come along with it, unless its the perfect male drug.
10-11-2006, 12:17 PM
10-12-2006, 12:30 PM
10-12-2006, 02:19 PM
10-13-2006, 02:29 PM
Indeed, the same compound is marketed as FARESTON in the US for treatment of advanced breast cancer and is in phase III trials for Adrogen Deprivation Therapy and Prostate Cancer under the ACAPODENE name.Originally Posted by faustus
10-13-2006, 03:14 PM
personally i am not too impressed with these compounds...it seems the main point of their creation is to provide the bone strengthening and muscle sustaining effects of steroids without the effect on cholesterol and androgenic side effects. this is sounds useful for cancer or aids...but not for bodbuilders
i love androgenic compounds, their effect on muscle hardness, strength, and agression are benefeits in my eyes, and i willingly accept the acne and truckloads of saw palmeto i need to buy to control benign prostate hypertophy.
also it states they are being considered for use as a form of male birth control, so they are obviously supressive. we already have primarily anabolic compounds such as anavar and primabolan, i am sure SARMS will prove a useful addition to an athletes/bodybuilder's arsenal, but i highly doubt they will replace conventional anabolic/androgenic steroids.
give me a SARM that doesnt raise my cholesterol, doesnt give me acne, doesnt supress me, doesnt make my prostate grow, improves my bone structure, aromatizes in the perfect amount, and gives me the mass building effects of m1t combined with the muscle hardness of tren or masteron and ill be impressed.
10-14-2006, 04:20 PM
How and why:Originally Posted by Random987
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. The AR ligand
binding domain is composed of 12 alpha-helices. In the
crystal structure, relatively few amino acid residues were
found to interact directly with the steroidal agonists, DHT
and methyltrienolone (R1881). 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. 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
.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
. 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
action may depend upon ligand-induced
AR conformation and recruitment of a tissue-specific repertoire
of coregulatory factors that function as coactivators corepressors.
Steroid Receptor Coactivators - Cutting Edge Muscle Forums
Steroid Receptor Coactivators
Selective Agonist Receptor Modulators - Cutting Edge Muscle Forums
Selective Agonist Receptor Modulators
10-16-2006, 01:00 PM
I think the advantages would be that it is orally available (no shots or gels), doesn't aramotize, doesn't convert to DHT, doesn't affect fertility, etc. In other words, it is more selective in its effects (sledgehammer v. scapel). It wouldn't be as much of a balancing act.
From the journal cited above:
Given the FDA, I don't believe we would get to this level in the near future, but wouldn't it make your job easier, if you could "design" a specific SARM for a particular patient, i.e. Jim wants anabolic effects, but doesn't want kids. John want anabolic effects, but wants kids, etc, etc.As shown in Figure 3, S-
4 acted as a full AR agonist in the levator ani muscle, as indicated its
ability to fully maintain the muscle to that of control level. However,
S-4 acted as a partial agonist in the prostate (Emax = 35% of control
values), indicating that S-4 was potent and efficacious in anabolic
tissues but not in androgenic tissues. In contrast, castrated rats
treated with testosterone propionate had near identical, and nonselective
growth of the prostate and levator ani muscle as compared
to control animals.
Originally Posted by Dr. John
12-14-2007, 08:14 PM
12-15-2007, 01:00 PM
The claims rule in a patent. For determining the scope of the patent, the description is almost irrelevant - it is there to provide support for the claims. If you want to know what kind of patent coverage they are going for, look at the claims. Narrower patent coverage is easier to get than broader patent coverage.
04-08-2008, 11:17 PM
A little bump. It looks like GTx (the leading SARM co.) has teamed up with Merck.
GTx, Inc. and Merck & Co., Inc. Enter Global Strategic Collaboration for the Development of SARMs, a Novel Investigational Class of Drugs to Treat Muscle Loss and other Musculoskeletal Conditions
MEMPHIS, Tenn. & WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--GTx, Inc. (NASDAQ: GTXI - News) and Merck & Co., Inc. (NYSE: MRK - News) today announced an agreement providing for a research and development and global strategic collaboration for selective androgen receptor modulators (SARMs), a new class of drugs with the potential to treat age-related muscle loss (sarcopenia) as well as other musculoskeletal conditions. This collaboration includes GTx's lead SARM candidate, Ostarine™, which is currently being evaluated in a Phase II clinical trial for the treatment of muscle loss in patients with cancer, and establishes a broad SARM collaboration under which GTx and Merck will pool their programs and partner to discover, develop, and commercialize current as well as future SARM molecules. As part of this global agreement, Merck will be responsible for all future costs associated with ongoing development and, if approved, commercialization of Ostarine and other investigational SARMs resulting from the collaboration.
Under the terms of the collaboration agreement and related stock purchase agreement, GTx and Merck will combine their respective SARM research programs. GTx will receive an upfront payment of $40 million plus $15 million in research reimbursements to be paid over the initial three years of the collaboration. In addition, Merck will make an equity investment of $30 million in GTx common stock at a 40 percent premium to the 30 day average closing price. GTx will also be eligible to receive up to $422 million in future milestone payments associated with the development and approval of a drug candidate if multiple indications receive regulatory approval. Additional milestones may be received for the development and approval of other collaboration drug candidates. GTx will receive royalties on any resulting worldwide product revenue.
“By combining our drug candidates, resources and talents, this Merck-GTx collaboration positions both companies for success in the development and commercialization of SARMs,” said Mitchell S. Steiner, M.D., chief executive officer of GTx. “We believe that Ostarine and our other SARMs offer the potential to address a number of unmet medical needs focused on musculoskeletal disorders. GTx believes that Merck has the world class scientific, clinical development, and commercial expertise to capture the potential of the SARM class.”
“By selectively targeting the androgen receptor, SARMs offer a promising alternative to androgen therapy with the potential advantages of oral dosing, tissue selectivity and improved safety and tolerability,” said Alan B. Ezekowitz, MBChB, D.Phil., senior vice president and franchise head, Bone, Respiratory, Immunology, and Endocrine, Merck Research Laboratories. "GTx has established a strong scientific reputation in the research and development of novel SARMs and we look forward to working with Dr. Steiner and his team."
The effectiveness of the collaboration agreement and the investment in GTx common stock by Merck are subject to the expiration or earlier termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act, if applicable, as well as other customary closing conditions.
GTx will host a conference call at 9 a.m. Eastern Time today to discuss the GTx-Merck collaboration as well as GTx's third quarter 2007 financial results. To listen to the conference call, please dial: 800-901-5248 from the United States and Canada or 617-786-4512 (International). The passcode for the call is #62291111.
A playback of the call will be available beginning today at 11:00 a.m. Eastern Time through November 20, and may be accessed by dialing: 888-286-8010 from the United States and Canada or 617-801-6888 (International). The reservation number for the replay is #89187183.
Selective androgen receptor modulators (SARM) are a new class of drugs with the potential to treat sarcopenia (age-related muscle loss) and other musculoskeletal conditions. Ostarine, a first in class SARM, has demonstrated the ability to build lean body mass (muscle) in a proof of concept clinical trial and may have the potential to improve physical performance. Ostarine is currently being evaluated in a Phase II clinical trial for the treatment of muscle loss in patients with cancer.
GTx, headquartered in Memphis, Tenn., is a biopharmaceutical company dedicated to the discovery, development, and commercialization of small molecules that selectively target hormone pathways to treat cancer, osteoporosis and bone loss, muscle wasting and other serious medical conditions. GTx is developing ACAPODENE® (toremifene citrate), a selective estrogen receptor modulator, or SERM, in two separate clinical programs in men: first, a pivotal Phase III clinical trial for the treatment of serious side effects of androgen deprivation therapy for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. GTx has licensed to Ipsen Limited exclusive rights in Europe to develop and commercialize ACAPODENE. GTx has agreed to a collaboration with Merck & Co., Inc. for the development and global commercialization of selective androgen receptor modulators, or SARMs, a new class of drugs with the potential to treat a variety of indications associated with muscle wasting and bone loss including sarcopenia and osteoporosis, cancer cachexia, and chronic kidney disease muscle wasting. GTx is also developing GTx-878, an estrogen receptor beta agonist for the treatment of benign prostatic hyperplasia and chronic prostatitis. GTx is planning to initiate human clinical studies for GTx-878 in 2009.
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicine to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit http://www.merck.com.
GTx Forward-Looking Statement
This press release contains forward-looking statements based upon GTx's current expectations, including all statements (i) that reflect the completion of the proposed collaboration with Merck (including statements related to GTx's receipt of upfront licensing fees, guaranteed preclinical development reimbursements, development and approval milestone payments and royalty payments, as well as proceeds from the sale of GTx common stock to Merck); and (ii) relating to the prospects for, and the development and commercialization of, Ostarine and other SARMs. Forward-looking statements involve risks and uncertainties. GTx's actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, the risks that (i) the collaboration agreement may not become effective and the investment by Merck in GTx common stock may not occur as a result of the failure to satisfy certain closing conditions under the agreements with Merck, including relating to the Hart-Scott-Rodino Antitrust Improvements Act of 1974; (ii) even if the collaboration agreement becomes effective, future payments to GTx may not be realized due to the inability to achieve certain milestones under the collaboration agreement or the failure to develop and commercialize Ostarine and other SARMs included in or arising from the collaboration; (iii) product candidates developed under the collaboration may not be commercialized as a result of the failure to obtain required regulatory approvals, including if clinical trials do not demonstrate safety and efficacy in humans; (iv) even if required regulatory approvals are obtained, products developed under the collaboration may not gain market acceptance among physicians, patients, health care payors and the medical community; and (v) GTx could utilize its available cash resources sooner than it currently expects and may be unable to raise capital when needed, which would force GTx to delay, reduce or eliminate its product development programs or commercialization efforts. You should not place undue reliance on these forward-looking statements, which apply only as of the date of this press release. GTx's quarterly report on form 10-Q filed with the U.S. Securities and Exchange Commission on August 1, 2007, contains under the heading "Risk Factors," a more comprehensive description of these and other risks to which GTx is subject. GTx expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.
Merck Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended December 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.
Graeme Bell, 1-908-423-5185
Ian R. McConnell, 1-908-423-3046
McDavid Stilwell, 901-507-2667
Source: Merck & Co., Inc.
04-09-2008, 02:46 AM
Isnt this what they are calling Jungle Warfare, a SARM? It is claimed to sensitizes androgen receptors, perhaps still in its infancy as it has the ability to also cause hair loss in some individuals.
06-09-2008, 03:25 PM
BTW, A recent study says that the prohormone 19-norandrostenedione displays selective androgen receptor modulator (SARM) like properties after subcutaneous administration:
The prohormone 19-norandrostenedione displays sele...[Toxicol Lett. 2008] - PubMed Result
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