1998-2004 SARMs Research

Androgen replacement in men with hypogonadism and erectile dysfunction.

Albrecht-Betancourt M, Hijazi RA, Cunningham GR.

Department of Medicine, Baylor College of Medicine and VA Medical Center, Houston, TX, USA.

The prevalence of hypogonadism and erectile dysfunction (ED) increases with age. Hypogonadism also is frequently associated with decreased libido and ED. Testosterone replacement therapy for hypogonadal ED is effective in restoring sexual desire and erectile function, especially in younger and healthy men. It appears to be less effective in older men with comorbid diseases that may cause ED. Therapy should be individualized, considered carefully, and closely monitored because of potential risks, especially in older men. The FDA has approved several testosterone delivery systems. These include a buccal testosterone tablet, intra-muscular injections, transdermal and subcutaneous forms. There also are several promising experimental androgens under investigation including non-steroidal selective androgen receptor modulators (SARMs). Copyright 2004 Humana Press Inc.


Design, synthesis, and biological characterization of metabolically stable selective androgen receptor modulators.

Marhefka CA, Gao W, Chung K, Kim J, He Y, Yin D, Bohl C, Dalton JT, Miller DD.

Department of Pharmaceutical Sciences, College of Pharmacy, Health Science Center, 847 Monroe Avenue, Johnson Building, Room 227C, The University of Tennessee, Memphis, Tennessee 38163, USA.

A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen receptor (AR). These ligands were designed to eliminate metabolic sites identified in one of our first-generation AR agonists, which was inactive in vivo due to its rapid metabolism to inactive constituents. The binding affinity of these compounds was evaluated using AR isolated from rat ventral prostate. These second-generation compounds bound the AR in a high affinity and stereoselective manner, with K(i) values ranging from about 4 to 130 nM. The ability of these ligands to stimulate AR-mediated transcriptional activation was examined in cells transfected with the human AR and a hormone-dependent luciferase reporter gene. Although some compounds were unable to stimulate AR-mediated transcription, several demonstrated activity similar to that of dihydrotestosterone (DHT, an endogenous steroidal ligand for the AR). We also evaluated the in vivo pharmacologic activity of selected compounds in castrated male rats. Three compounds were identified as selective androgen receptor modulators (SARMs), exhibiting significant anabolic activity while having only moderate to minimal androgenic activity in vivo.


Role of androgens in mild cognitive impairment and possible interventions during andropause.

Tan RS, Pu SJ, Culberson JW.

Department of Family and Community Medicine, University of Texas Medical School and Garden Terrace Alzheimer’s Center, 6431 Fannin Street, JJL Suite 308, Houston, TX 77030, USA. [email protected]

Mild cognitive impairment (MCI) is becoming fashionable as a diagnosis, representing a state of cognitive decline associated with negligible functional loss. MCI is important as it often precedes Alzheimer’s disease (AD). Recognizing MCI may lead to preventive strategies that can delay the onset of AD. Many patients who transition into andropause report problems with their memory. There is strong evidence from basic sciences and epidemiological studies that both estrogens and androgens play a protective role in neurodegeneration. The evidence from small prospective clinical trials lends support to the role of hormones in improving cognitive function. The improvement in cognitive function with hormones is subtle and often not measurable on standard neuropsychological batteries. Patients have reported memory improvements in both declarative and procedural domains after being on hormonal replacement. Functional changes and vascular changes can be detected after hormonal replacement with more sophisticated imaging of the brain like PET scans. We hypothesize androgens and perhaps selective androgen receptor modulators as future treatment options for MCI in aging males.


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.


Antiandrogens: selective androgen receptor modulators.

Berrevoets CA, Umar A, Brinkmann AO.

Department of Reproduction and Development, Erasmus University Medical Centre Rotterdam, PO Box 1738, DR-3000 Rotterdam, The Netherlands.

Antiandrogens can efficiently block androgen receptor (AR) mediated gene expression, and are therefore useful tools in the treatment of androgen dependent prostate cancer. Antiandrogens are either complete or partial inhibitors of AR activity, depending on the nature of the compound. As compared to androgens, antiandrogens induce a different AR conformation, thereby influencing the recruitment of co-regulators (coactivators and corepressors). This ligand-selective modulation of AR activity is affected by an AR mutation (Thr877Ala substitution) found in prostate cancer. In contrast to the wild-type AR, the mutant AR conformation induced by cyproterone acetate (CPA) and hydroxyflutamide (OHF) is comparable to that induced by androgens. As a consequence, this might affect recruitment of co-regulators, thereby allowing CPA and OHF to act as strong agonists on the mutant AR. Copyright 2002 Elsevier Science Ireland Ltd.


Antiandrogens in prostate cancer.

Reid P, Kantoff P, Oh W.

Lank Center for Genitourinary Oncology, Dana Farber-Partners Cancer Care, Boston, MA 02115, USA.

Antiandrogens competitively inhibit ligand binding to the androgen receptor (AR), and are used therapeutically in prostate cancer patients. The AR functions as a ligand dependent transcription factor that transduces androgen binding into increased transcription of androgen dependent genes. AR blockade induces programmed cell death in the vast majority of malignant and benign prostate cancer cells that have not previously been exposed to androgen ablation. The antiandrogens are divided structurally into the steroidal and non steroidal agents. The biological effects of the steroidal versus nonsteroidal agents are distinguished by differences in their effects on serum testosterone levels, and by their activity at receptors other than the androgen receptor. There is extensive clinical experience in the palliative and curative therapy of prostate cancer using antiandrogens as monotherapy or antiandrogens in combination with luteinizing hormone agonists or surgical castration. Prolonged therapy with antiandrogens selects for mutations in the AR that change the AR ligand specificity and permits stimulation by ligands that are usually inhibitory. These mutations give insight into one of the means by which prostate cancer progresses despite antiandrogen therapy, and also helps to explain the antiandrogen withdrawal syndrome. Areas of active research that may affect the future use of antiandrogens include the ongoing evaluation of antiandrogens in combination with 5 alpha reductase inhibitors to achieve AR blockade without inducing castrate testosterone levels. There is also interest in developing selective androgen receptor modulators (SARM) that can achieve AR blockade without causing the increased testosterone levels produced by the nonsteroidal antiandrogens currently in use.