Development of selective androgen receptor modulators (SARMs)

• Published in: Molecular and cellular endocrinology Vol. 465; pp. 134 - 142
• Main Authors: Narayanan, Ramesh, Coss, Christopher C., Dalton, James T.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.04.2018
• Subjects: adverse effects; androgen receptors; Androgens; Breast cancer; breast neoplasms; Coactivators; cross reaction; Duchenne muscular dystrophy (DMD); evolution; Kinase; ligands; mechanism of action; metabolism; Muscle wasting; osteoporosis; Selective androgen receptor modulators (SARMs); Stress urinary incontinence; testosterone; tissues; Androgens; Selective androgen receptor modulators (SARMs); Kinase; Muscle wasting; Coactivators; Duchenne muscular dystrophy (DMD); Breast cancer; Stress urinary incontinence
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2017.06.013

The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits. •Review of the status of SARM development.•Molecular mechanisms of tissue selectivity.•Challenges to regulatory approval of SARMs for therapeutic use.