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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.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.

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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Related in: MedlinePlus

SARM templates from GlaxoSmithKline (GSK).GSK patented an assortment of aniline SARMs (47-54) without specific SARM characterization, but rather just in vitro data.  The aniline (55) was characterized in vitro as an AR agonist.  Separately, GSK reported in conference abstracts in vitro characterizations of benzoxazepines as AR agonists.  GSK has reported their first public disclosure of SARM activity in a conference abstract for GSK2420A (structure not known), and is pursuing GSK971086 (structure not known) as a clinical candidate.  Although there is not much public information from GSK, the breadth of their patents and presentations suggests that they have an active SARM program.
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fig8: SARM templates from GlaxoSmithKline (GSK).GSK patented an assortment of aniline SARMs (47-54) without specific SARM characterization, but rather just in vitro data. The aniline (55) was characterized in vitro as an AR agonist. Separately, GSK reported in conference abstracts in vitro characterizations of benzoxazepines as AR agonists. GSK has reported their first public disclosure of SARM activity in a conference abstract for GSK2420A (structure not known), and is pursuing GSK971086 (structure not known) as a clinical candidate. Although there is not much public information from GSK, the breadth of their patents and presentations suggests that they have an active SARM program.

Mentions: GSK patents outline a wide variety of disubstituted aniline templates to include para nitro/cyano and ortho/meta electron withdrawing A-ring substituents on a phenyl A-ring. Examples of the structural diversity of this series are given in Figure 8 with the following compounds: (47-48) (US patent application US2006 0148893 [Blanc et al., 2006]), (49) (World patent application WO2005 000795 [Blanc et al., 2005]), (50) (World patent application WO2005 085185 [Turnbull et al., 2005]), (51-52) (World patent application WO2006 133216 [Turnbull et al., 2006]). Alternatively, these compounds have para nitro/cyano naphthyl A-rings such as (53-54) (US patent application US2006 0142387 [Cadilla et al., 2006]). The aniline substituents of these templates include alkyl, haloalkyl, alkenyl, cycloalkyl, alkanol, alkylamino, and carboxylate and derivatives (Figure 8). The patents describe GR, PR, MR, and AR binding affinity and AR-luciferase transactivation in vitro assays and in vivo studies in castrated rats analyzing VP and SV, LA and bulbocavernosus (BC) muscles as androgenic and anabolic indicators, respectively. However, the only GSK disubstituted aniline for which biological data is disclosed is a nilutamide-like cyclic aniline template [Trump et al., 2007]. A virtual screening-guided combinatorial chemistry approach was used to find AR agonists with various substitutions of the left ring and various replacements of the right ring, as shown, of compound (55). This yielded 352 submicromolar and 17 subnanomolar AR agonists, as measured by a cell-based reporter gene functional assay.


Selective androgen receptor modulators in preclinical and clinical development.

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

SARM templates from GlaxoSmithKline (GSK).GSK patented an assortment of aniline SARMs (47-54) without specific SARM characterization, but rather just in vitro data.  The aniline (55) was characterized in vitro as an AR agonist.  Separately, GSK reported in conference abstracts in vitro characterizations of benzoxazepines as AR agonists.  GSK has reported their first public disclosure of SARM activity in a conference abstract for GSK2420A (structure not known), and is pursuing GSK971086 (structure not known) as a clinical candidate.  Although there is not much public information from GSK, the breadth of their patents and presentations suggests that they have an active SARM program.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: SARM templates from GlaxoSmithKline (GSK).GSK patented an assortment of aniline SARMs (47-54) without specific SARM characterization, but rather just in vitro data. The aniline (55) was characterized in vitro as an AR agonist. Separately, GSK reported in conference abstracts in vitro characterizations of benzoxazepines as AR agonists. GSK has reported their first public disclosure of SARM activity in a conference abstract for GSK2420A (structure not known), and is pursuing GSK971086 (structure not known) as a clinical candidate. Although there is not much public information from GSK, the breadth of their patents and presentations suggests that they have an active SARM program.
Mentions: GSK patents outline a wide variety of disubstituted aniline templates to include para nitro/cyano and ortho/meta electron withdrawing A-ring substituents on a phenyl A-ring. Examples of the structural diversity of this series are given in Figure 8 with the following compounds: (47-48) (US patent application US2006 0148893 [Blanc et al., 2006]), (49) (World patent application WO2005 000795 [Blanc et al., 2005]), (50) (World patent application WO2005 085185 [Turnbull et al., 2005]), (51-52) (World patent application WO2006 133216 [Turnbull et al., 2006]). Alternatively, these compounds have para nitro/cyano naphthyl A-rings such as (53-54) (US patent application US2006 0142387 [Cadilla et al., 2006]). The aniline substituents of these templates include alkyl, haloalkyl, alkenyl, cycloalkyl, alkanol, alkylamino, and carboxylate and derivatives (Figure 8). The patents describe GR, PR, MR, and AR binding affinity and AR-luciferase transactivation in vitro assays and in vivo studies in castrated rats analyzing VP and SV, LA and bulbocavernosus (BC) muscles as androgenic and anabolic indicators, respectively. However, the only GSK disubstituted aniline for which biological data is disclosed is a nilutamide-like cyclic aniline template [Trump et al., 2007]. A virtual screening-guided combinatorial chemistry approach was used to find AR agonists with various substitutions of the left ring and various replacements of the right ring, as shown, of compound (55). This yielded 352 submicromolar and 17 subnanomolar AR agonists, as measured by a cell-based reporter gene functional assay.

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.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.

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