Selective androgen receptor modulators as function promoting therapies.
OBJECTIVE
The past decade has witnessed an unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity.


RESULTS
Although steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5alpha-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with androgen receptor (AR) contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand-binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass.


CONCLUSIONS
SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis.
Section of Endocrinology, Diabetes, and Nutrition, Boston Claude D. Pepper Older Americans Independence Center for Function Promoting Therapies, Boston University School of Medicine, Boston, Massachusetts, USA. Bhasin@bu.edu
Shalender
S
Bhasin
Ravi
R
Jasuja
D000726:Androgen Antagonists / Q000627:therapeutic use; D000728:Androgens; D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000819:agonists / Q000031:analogs & derivatives
D000726:Androgen Antagonists; D000728:Androgens; D008024:Ligands; D011944:Receptors, Androgen; D013739:Testosterone