Selective androgen receptor modulators in preclinical and clinical development

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.

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Selective androgen receptor modulators (SARMs) have specific impacts on the mouse uterus

Journal of Endocrinology ◽

10.1530/joe-19-0153 ◽

2019 ◽

Vol 242 (3) ◽

pp. 227-239 ◽

Cited By ~ 2

Author(s):

Ioannis Simitsidellis ◽

Arantza Esnal-Zuffiaure ◽

Olympia Kelepouri ◽

Elisabeth O’Flaherty ◽

Douglas A Gibson ◽

...

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Androgen Receptor ◽

Muscle Wasting ◽

Tissue Architecture ◽

Mouse Uterus ◽

Minimal Impact ◽

Selective Androgen Receptor Modulators ◽

The Impact ◽

Receptor Modulators

Selective androgen receptor modulators (SARMs) have been proposed as therapeutics for women suffering from breast cancer, muscle wasting or urinary incontinence. The androgen receptor (AR) is expressed in the uterus but the impact of SARMs on the function of this organ is unknown. We used a mouse model to compare the impact of SARMs (GTx-007/Andarine®, GTx-024/Enobosarm®), Danazol (a synthetic androstane steroid) and dihydrotestosterone (DHT) on tissue architecture, cell proliferation and gene expression. Ovariectomised mice were treated daily for 7 days with compound or vehicle control (VC). Uterine morphometric characteristics were quantified using high-throughput image analysis (StrataQuest; TissueGnostics), protein and gene expression were evaluated by immunohistochemistry and RT-qPCR, respectively. Treatment with GTx-024, Danazol or DHT induced significant increases in body weight, uterine weight and the surface area of the endometrial stromal and epithelial compartments compared to VC. Treatment with GTx-007 had no impact on these parameters. GTx-024, Danazol and DHT all significantly increased the percentage of Ki67-positive cells in the stroma, but only GTx-024 had an impact on epithelial cell proliferation. GTx-007 significantly increased uterine expression of Wnt4 and Wnt7a, whereas GTx-024 and Danazol decreased their expression. In summary, the impact of GTx-024 and Danazol on uterine cells mirrored that of DHT, whereas GTx-007 had minimal impact on the tested parameters. This study has identified endpoints that have revealed differences in the effects of SARMs on uterine tissue and provides a template for preclinical studies comparing the impact of compounds targeting the AR on endometrial function.

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Myoanabolic steroids and selective androgen receptor modulators: mechanism of action and perspectives

Orvosi Hetilap ◽

10.1556/oh.2009.28739 ◽

2009 ◽

Vol 150 (45) ◽

pp. 2051-2059 ◽

Cited By ~ 2

Author(s):

Miklós Tóth

Keyword(s):

Skeletal Muscle ◽

Androgen Receptor ◽

Conformational Changes ◽

Anabolic Steroids ◽

Target Tissue ◽

Androgenic Activity ◽

Selective Androgen Receptor Modulators ◽

Transcriptional Coregulators ◽

Tissue Selectivity ◽

Receptor Modulators

Interest in anabolic steroids has been renewed in the last decade with the discovery of tissue-selective androgen receptor modulators exhibiting high myotropic and small androgenic activity. An explanation put forward by us in 1982 for the mechanism of the preferential myotropic effect of nandrolone (19-nortestosterone) exploits the fundamental difference between the 5α-reductase concentrations in skeletal muscle and androgenic target tissue. In androgenic tissue, testosterone is converted to the more potent 5α-dihydrotestosterone whereas nandrolone is converted to a less potent derivative. As 5α-reduction is negligible in skeletal muscle, this explains why nandrolone shows a greater myotropic to androgenic ratio when compared with testosterone. Anabolic steroids that do not undergo 5α-reduction exert myotropic-androgenic dissociation because their effect in androgenic tissues is not amplified by 5α-reduction. Tissue selectivity by receptor modulators may be achieved by inducing specific conformational changes of the androgen receptor that affect its interaction with transcriptional coregulators. Anabolic activity is mediated by the stimulation of ribosomal RNA synthesis therefore regulation of this synthesis by anabolic steroids would deserve detailed studies.

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