Discovery and therapeutic promise of selective androgen receptor modulators

Abstract

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.

Figure 1. Hypothalamus-pituitary-testis axis of androgen regulation

The production of testosterone is regulated by hormones produced from hypothalamus and pituitary. (+) represents positive feedback and (−) represents negative feedback.

Figure 2

Chemical structures of hydroxyflutamide, bicalutamide, aryl proprionamide ligands.

Figure 3. Tissue-selective pharmacologic activity of S-4

A. Male rats were castrated and treated for 14 consecutive days with S-4. S-4 potently stimulates muscle growth, but is unable to maintain prostate size. Adapted from J. Pharmacol. Exp. Therap. 304, 1334 (2005). B. Testosterone stimulates muscle and prostate growth to the same extent.