Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs)

Abstract

Selective androgen receptor modulators (SARMs) are a novel class of androgen receptor (AR) ligands that might change the future of androgen therapy dramatically. With improved pharmacokinetic characteristics and tissue-selective pharmacological activities, SARMs are expected to greatly extend the clinical applications of androgens to osteoporosis, muscle wasting, male contraception and diseases of the prostate. Mechanistic studies with currently available SARMs will help to define the contributions of differential tissue distribution, tissue-specific expression of 5alpha-reductase, ligand-specific regulation of gene expression and AR interactions with tissue-specific coactivators to their observed tissue selectivity, and lead to even greater expansion of selective anabolic therapies.

FIGURE 1

Three modes of action of T. T might act directly through ARs, be converted to DHT by 5α-reductase before binding to ARs, and be aromatized to estrogen and act through the ER.

FIGURE 2

Tissue-specific expression of 5α-reductase contributes to the tissue selectivity of SARMs. (a) Partial agonist activity of T in the prostate when co-administered with finasteride, a type 2 5α-reductase inhibitor. Redrawn with permission from Ref. [22]. (b) Partial agonist activity of a SARM (aryl propionamide analog S-4) in the prostate when administered alone. Redrawn with permission from Ref. [54]. (c) Full agonist activity of the aryl propionamide analog S-4 in the levator ani muscle. Redrawn with permission from Ref. [54]. Data in (a) was obtained using a prostate regrowth model in castrated rats [22], whereas data in (b,c) were obtained using a prostate maintenance model in castrated rats [54]. Because S-4 has similar effects in maintenance [54] and re-growth [60] models, the more detailed dose–response data from the maintenance model are used in (b) and (c).