2007 SARMs Research

The latest options and future agents for treating male hypogonadism.

Edelstein D, Sivanandy M, Shahani S, Basaria S.

Johns Hopkins University School of Medicine, Division of Endocrinology and Metabolism, Bayview Medical Center, 5200 Eastern Avenue, Mason F Lord Building, 4th Floor, Suite 4300, Baltimore, Maryland 21224, USA.

Exogenous testosterone has long been used in medicine as a pharmaceutical agent. Its use in hypogonadism is well characterized and its development as a drug has undergone several modifications in an attempt to achieve clinical success. As native testosterone is rapidly degraded, modified analogs have been developed to obtain a better pharmacokinetic profile. The developmental goals of testosterone analogs have evolved since its first introduction as an orally available form to longer acting and more stable forms such as injectables, depots and transdermal therapies. Several modalities of testosterone replacement are presently available, each differentiated by their route of delivery, half life, cost and ability to deliver physiologic levels of testosterone. As hypogonadism is often a life-long condition, physicians are compelled to use an appropriate therapy that best matches the needs of their patients. An ideal testosterone therapy should be able to deliver physiologic levels of testosterone and be safe, simple to use and cost effective. Present trends show transdermal therapies (gels and patches) along with long-acting injectables, such as Nebido, are quickly replacing intramuscular testosterone modalities. Compounds such as dihydrotestosterone, human chorionic gonadotropin, aromatase inhibitors and clomiphene are presently being studied in specific subgroups of men. Additionally, several new compounds, such as selective androgen-receptor modulators and 7-alpha-methyl-19-nortestosterone, are being developed to target androgen receptors in specific tissues. A further understanding of the androgen receptor and subsequent discovery of targeted drugs may yield more individualized treatment modalities. This will enhance the effectiveness of available therapies, while mitigating their undesirable effects.


A selective androgen receptor modulator with minimal prostate hypertrophic activity enhances lean body mass in male rats and stimulates sexual behavior in female rats.

Allan GF, Tannenbaum P, Sbriscia T, Linton O, Lai MT, Haynes-Johnson D, Bhattacharjee S, Zhang X, Sui Z, Lundeen SG.

Reproductive Therapeutics, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ, 08869, USA. [email protected]

Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-28330835 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle, stimulating maximal growth at a dose of 10 mg/kg. At the same time, JNJ-28330835 reduced prostate weight in intact rats by a mean of 30% at 10 mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging (MRI) to monitor body composition, it prevented half of the loss of lean body mass associated with orchidectomy, and restored about 30% of lost lean mass to aged orchidectomized rats. It had agonist effects on markers of both osteoclast and osteoblast activity, suggesting that it reduces bone turnover. In a model of sexual behavior, JNJ-28330835 enhanced the preference of ovariectomized female rats for sexually intact male rats over nonsexual orchidectomized males. JNJ-28330835 is a prostate-sparing SARM with the potential for clinically beneficial effects in muscle-wasting diseases and sexual function disorders.


Screening for 2-quinolinone-derived selective androgen receptor agonists in doping control analysis.

Thevis M, Kohler M, Maurer J, Schlörer N, Kamber M, Schänzer W.

Center for Preventive Doping Research-Institute of Biochemistry, German Sport University Cologne, Carl-Diem Weg 6, 50933 Cologne, Germany. [email protected]

Selective androgen receptor modulators (SARMs) represent a class of emerging drugs with high potential for misuse in sports, and therefore members of this group are banned as anabolic agents by the World Anti-Doping Agency. Preventive approaches to restrict their use include early implementation of target analytes into doping control screening assays and evaluation of the mass spectrometric behavior of these drugs to allow their unequivocal identification as well as the characterization of structurally related compounds and metabolic products. Four model SARMs with the 6-alkylamino-2-quinolinone structure, including the advanced drug candidate LGD-2226, were synthesized. Fragmentation pathways after positive electrospray ionization and collision-induced dissociation were studied using an LTQ Orbitrap mass analyzer, and diagnostic product ions and common dissociation pathways were employed to establish a screening procedure targeting intact quinolinone-based SARMs as well as putative metabolic products such as dealkylated analogues. Therefore, features of a triple quadrupole mass analyzer such as multiple reaction monitoring and precursor ion scanning were utilized. Sample preparation based on commonly employed liquid-liquid extraction and subsequent liquid chromatographic/tandem mass spectrometric measurement allowed for detection limits of 0.01-0.2 ng/mL, and intra- and interday precisions between 3.2 and 8.5% and between 6.3 and 16.6%, respectively. Recoveries varied from 81 to 98%, and tests for ion suppression or enhancement effects were negative for all analytes. Copyright (c) 2007 John Wiley & Sons, Ltd.


Androgens in the etiology of Alzheimer’s disease in aging men and possible therapeutic interventions.

Fuller SJ, Tan RS, Martins RN.

Centre of Excellence for Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.

Animal experiments and cell biology studies have provided evidence that both estrogens and androgens can play a protective role against Alzheimer’s disease (AD) related neurodegeneration. Males who become hypogonadal in later life often report problems with their memory. Lower than normal testosterone levels have also been detected in patients prior to the onset of AD, as well as in younger late-onset male AD patients, when compared to appropriate controls. The results of some small clinical trials suggest that testosterone can improve cognitive function in andropause. Although such improvement in cognitive function is subtle, patients on testosterone replacement therapy have reported memory improvements in both declarative and procedural domains. In contrast, there is no clinical evidence to date which suggest that the hormone dihydroepiandrosterone (DHEA) can improve cognitive function. Rises in the levels of the gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), have been associated with AD, but the clinical effects of reducing their levels remain to be determined. We hypothesize that androgens, gonadotropin modulators, or perhaps selective androgen receptor modulators may be useful components of therapy aimed at preventing the onset or delaying the progression of AD in male patients.


Selective androgen receptor modulators for frailty and osteoporosis.

Kilbourne EJ, Moore WJ, Freedman LP, Nagpal S.

Women’s Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.

Androgens play an important role not only in male sexual differentiation, puberty, sexual behavior and spermatogenesis, but also in the maintenance of bone architecture and muscle mass and strength. For decades, steroidal androgens have been used by hypogonadal and aging men as hormone replacement therapy, and abused by prominent athletes as anabolic agents for enhancing physical performance. The use of steroidal androgens is associated with hepatotoxicity, potential for prostate stimulation, virilizing actions and other side effects resulting from their cross-reactivity to related steroid receptors. Therefore, to utilize the therapeutic potential of the androgen receptor for the treatment of indications such as osteoporosis and frailty, several pharmaceutical and biotechnology companies are developing non-steroidal tissue-selective androgen receptor modulators (SARMs) that retain the beneficial properties of natural androgens and exhibit better therapeutic indices. This article reviews the mechanism of androgen action, novel non-steroidal ligands under development and future directions of SARM research for the discovery of novel modulators for frailty and osteoporosis.


Hormone replacement Up-to-date. Selective androgen receptor modulators (SARMs). Current status and their future

Tsukamoto T, Kato R, Kobayashi K.

Sapporo Medical University School of Medicine, Department of Urology, Japan.

Selective androgen receptor modulators (SARMs) with tissue or organ-specificity are expected for their development. Indeed, they will be widely applied for patients with late onset of hypodonadism and those with prostate cancer who have hormone treatment-induced osteoporosis. SARMs having anabolic action on the bone or muscle but no or weak androgenic action on the prostate will be welcomed in the clinical setting.


Potent, nonsteroidal selective androgen receptor modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones.

Higuchi RI, Thompson AW, Chen JH, Caferro TR, Cummings ML, Deckhut CP, Adams ME, Tegley CM, Edwards JP, López FJ, Kallel EA, Karanewsky DS, Schrader WT, Marschke KB, Zhi L.

Discovery Research, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA. [email protected]

A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.


Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications.

Li JJ, Sutton JC, Nirschl A, Zou Y, Wang H, Sun C, Pi Z, Johnson R, Krystek SR Jr, Seethala R, Golla R, Sleph PG, Beehler BC, Grover GJ, Fura A, Vyas VP, Li CY, Gougoutas JZ, Galella MA, Zahler R, Ostrowski J, Hamnn LG.

Discovery Chemistry, Computer Assisted Drug Design, Metabolic Disease Research, Metabolism and Pharmacokinetics, Discovery Analytical Sciences, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. [email protected]

A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.


Emerging drugs–potential for misuse in sport and doping control detection strategies.

Thevis M, Schänzer W.

Institute of Biochemistry – Center for Preventive Doping Research, German Sport University Cologne, Carl-Diem Weg 6, 50933 Cologne, Germany. [email protected]

Preventive doping research includes the development of methods for the detection of new or emerging drugs to be implemented in routine screening analysis. Candidates with great potential for misuse in elite sports include selective androgen receptor modulators, growth hormone secretagogues, hypoxia-inducible factor stabilizers and erythropoietin mimetics.


Doping. High-tech cheating in sport

Striegel H, Simon P.

Abteilung Sportmedizin, Medizinische Universitätsklinik Tübingen. [email protected]

Today, doping is no longer limited to the classical drugs with well known effects and side effects. Older generation anabolic steroids are used mainly in fitness and recreational sports. In contrast, due to doping tests, substances used in competitive sports include peptide hormones, medications not yet approved, and even specially developed drugs, such as designer steroids. Of the peptide hormones, particularly growth hormones (human growth hormone), erythropoietin and generics, insulin, and presumably insulin-like growth factor 1 are used. Substance groups potentially relevant for doping are selective androgen receptor modulators and gene therapy drugs. For most of these, there is no knowledge about side effects in healthy individuals, and no adequate doping tests. Therefore, anti-doping measures cannot rely solely on the continual improvement of doping analyses, but should include increased measures for doping prevention. Not only sports organizations, but also governmental agencies should be involved in developing and implementing these measures.


Ockham’s razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase?

Gao W, Dalton T.

Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo SUNY, Buffalo, NY 14260, USA.

Selective Androgen Receptor Modulators (SARMs) are a novel class of AR ligands that possess tissue-selective pharmacological activities. SARMs of various chemical structures have been discovered and characterized, and lead compounds with much improved specificity for AR, in vivo pharmacokinetic profiles, and higher degree of tissue selectivity have entered clinical development, and are expected to dramatically expand the clinical applications of androgens. With the rapid progress in SARM discovery and increasing demand for mechanism-based drug design, more and more research efforts have been devoted to the mechanisms of action of the observed tissue selectivity of SARMs. There is increasing enthusiasm in adapting the molecular mechanisms of action from SERM research to the SARM field; however, is the SARM story really so complicated? The tissue-specific expression of 5alpha-reductase might provide a simple explanation for this puzzle.


Synthesis of potent and tissue-selective androgen receptor modulators (SARMs): 2-(2,2,2)-Trifluoroethyl-benzimidazole scaffold.

Ng RA, Lanter JC, Alford VC, Allan GF, Sbriscia T, Lundeen SG, Sui Z.

Johnson & Johnson Pharmaceutical Research and Development, LLC, Drug Discovery, 665 Stockton Drive, Exton, PA 19341, USA.

The synthesis and in vivo SAR of 2-(2,2,2)-trifluoroethyl-benzimidazoles are described. Prostate antagonism and/or levator ani agonism can be modulated by varying the substitution at the 2-position of 5,6-dichloro-benzimidazoles. Potent androgen agonists on the muscle were discovered that strongly bind to the androgen receptor (2-17 nM) and show potent in vivo efficacy (0.03-0.11 mg/day). True SARMs showing both prostate antagonism and levator ani agonism were revealed.