2005 SARMs Research

Advances in male hormone substitution therapy.

Qoubaitary A, Swerdloff RS, Wang C.

Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA 90509, USA.

Increased awareness of the clinical diagnosis of male hypogonadism has resulted in the wider use of androgen substitution therapy. Clinical signs and symptoms together with a low serum testosterone level confirm the diagnosis of male hypogonadism. Androgen replacement results in improved sexual function, mood, muscle mass and bone density in most hypogonadal men. Such benefits must be assessed against potential risks. In older men, the potential risks of androgen treatment of hypogonadism are not known. Many delivery systems for androgen substitution are now available; the preparation chosen depends on the choice of the patient and his physician. Selective androgen receptor modulators offer tissue selective biological effects and the possibility of attaining maximum efficacy and minimum adverse effects.


Discovery and therapeutic promise of selective androgen receptor modulators.

Chen J, Kim J, Dalton JT.

Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA. [email protected]

Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects.


A selective androgen receptor modulator for hormonal male contraception.

Chen J, Hwang DJ, Bohl CE, Miller DD, Dalton JT.

College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies, including hormonal male contraception. The identification of an orally bioavailable SARM with the ability to mimic the central and peripheral androgenic and anabolic effects of testosterone would represent an important step toward the “male pill”. We characterized the in vitro and in vivo pharmacologic activity of (S)-3-(4-chloro-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (C-6), a novel SARM developed in our laboratories. C-6 was identified as an androgen receptor (AR) agonist with high AR binding affinity (K(i) = 4.9 nM). C-6 showed tissue-selective pharmacologic activity with higher anabolic activity than androgenic activity in male rats. The doses required to maintain the weight of the prostate, seminal vesicles, and levator ani muscle to half the size of the maximum effects (i.e., ED(50)) were 0.78 +/- 0.06, 0.88 +/- 0.1, and 0.17 +/- 0.04 mg/day, respectively. As opposed to other SARMs, gonadotropin levels in C-6-treated groups were significantly lower than control values. C-6 also significantly decreased serum testosterone concentration in intact rats after 2 weeks of treatment. Marked suppression of spermatogenesis was observed after 10 weeks of treatment with C-6 in intact male rats. Pharmacokinetic studies of C-6 in male rats revealed that C-6 was well absorbed after oral administration (bioavailability 76%), with a long (6.3 h) half-life at a dose of 10 mg/kg. These studies show that C-6 mimicked the in vivo pharmacologic and endocrine effects of testosterone while maintaining the oral bioavailability and tissue-selective actions of nonsteroidal SARMs.