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Selective androgen receptor modulators in preclinical and clinical development.

Narayanan R, Mohler ML, Bohl CE, Miller DD, Dalton JT - Nucl Recept Signal (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Preclinical Research and Development, GTx, Inc., Memphis, Tennessee, USA.

ABSTRACT
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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Discovery of propionamide AR agonists in vitro and in vivo.The nonsteroidal antiandrogens (1-4) demonstrate therapeutic utility in prostate cancer, and are structurally similar to some nonsteroidal tissue-selective agonists (i.e., SARMs).  An early example of which was (5), which was vastly improved by thioether to ether conversion, resulting in the prototypic SARM, S-4 (6).  Preclinical characterizations of this molecule catalyzed the development of the SARM field, as discussed herein and in the literature in general.
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fig2: Discovery of propionamide AR agonists in vitro and in vivo.The nonsteroidal antiandrogens (1-4) demonstrate therapeutic utility in prostate cancer, and are structurally similar to some nonsteroidal tissue-selective agonists (i.e., SARMs). An early example of which was (5), which was vastly improved by thioether to ether conversion, resulting in the prototypic SARM, S-4 (6). Preclinical characterizations of this molecule catalyzed the development of the SARM field, as discussed herein and in the literature in general.

Mentions: The field of nonsteroidal androgens, and especially selective androgen receptor modulators (SARMs), has grown tremendously since the first report in 1998. Many of the major pharmaceutical companies have now published in vivo characterizations of tissue selective AR agonists, and the rate of new contributions to this field continues to accelerate. The expansion of the field has resulted in a broadening of the chemical space originally occupied by the traditional steroidal agonists (not shown) and nonsteroidal antagonists (compounds (1), (2), (3), and (4); Figure 2), whose use is limited by prostate liability and lack of tissue-selectivity, respectively.


Selective androgen receptor modulators in preclinical and clinical development.

Narayanan R, Mohler ML, Bohl CE, Miller DD, Dalton JT - Nucl Recept Signal (2008)

Discovery of propionamide AR agonists in vitro and in vivo.The nonsteroidal antiandrogens (1-4) demonstrate therapeutic utility in prostate cancer, and are structurally similar to some nonsteroidal tissue-selective agonists (i.e., SARMs).  An early example of which was (5), which was vastly improved by thioether to ether conversion, resulting in the prototypic SARM, S-4 (6).  Preclinical characterizations of this molecule catalyzed the development of the SARM field, as discussed herein and in the literature in general.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2602589&req=5

fig2: Discovery of propionamide AR agonists in vitro and in vivo.The nonsteroidal antiandrogens (1-4) demonstrate therapeutic utility in prostate cancer, and are structurally similar to some nonsteroidal tissue-selective agonists (i.e., SARMs). An early example of which was (5), which was vastly improved by thioether to ether conversion, resulting in the prototypic SARM, S-4 (6). Preclinical characterizations of this molecule catalyzed the development of the SARM field, as discussed herein and in the literature in general.
Mentions: The field of nonsteroidal androgens, and especially selective androgen receptor modulators (SARMs), has grown tremendously since the first report in 1998. Many of the major pharmaceutical companies have now published in vivo characterizations of tissue selective AR agonists, and the rate of new contributions to this field continues to accelerate. The expansion of the field has resulted in a broadening of the chemical space originally occupied by the traditional steroidal agonists (not shown) and nonsteroidal antagonists (compounds (1), (2), (3), and (4); Figure 2), whose use is limited by prostate liability and lack of tissue-selectivity, respectively.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Preclinical Research and Development, GTx, Inc., Memphis, Tennessee, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus