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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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SARMs patented by Lilly, Pfizer, and Acadia.Lilly patented two SARM templates, the N-arylpyrrolidines and tetrahydrocarbazoles, which they characterize as tissue-selective.  Unfortunately, their comparisons are to vehicle-treated animals, making it hard to assess the relative activity compared to other templates.  Pfizer likewise has patented an aniline series of SARMs, which they characterize as high affinity and tissue-selective full agonists.  Acadia too has patented a novel SARM template of [3.2.1] tricyclic anilines, which they characterize as weak anabolic agents that suppress LH at therapeutic doses.
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fig9: SARMs patented by Lilly, Pfizer, and Acadia.Lilly patented two SARM templates, the N-arylpyrrolidines and tetrahydrocarbazoles, which they characterize as tissue-selective. Unfortunately, their comparisons are to vehicle-treated animals, making it hard to assess the relative activity compared to other templates. Pfizer likewise has patented an aniline series of SARMs, which they characterize as high affinity and tissue-selective full agonists. Acadia too has patented a novel SARM template of [3.2.1] tricyclic anilines, which they characterize as weak anabolic agents that suppress LH at therapeutic doses.

Mentions: Substituted N-arylpyrrolidines: Lilly scientists patented a series of substituted N-arylpyrrolidines as a SARM template (World patent application WO2006 124447 [Gavardinas et al., 2006]). In vitro activity was reported for numerous compounds to achieve low nM AR binding with several potent transcriptional activators that approach full agonist efficacy in C2C12 cells as an indicator of agonist activity in muscle tissue. The in vivo activity was reported for two compounds (59) (reportedly commercially available) and (60), which were tested in castrated (at 8 weeks) mice after 8 weeks of wasting (Figure 9). Test animals were dosed over a two week timeframe at 0.3, 1, 3, 10, and 30 mg/kg per day by mouth (i.e., per os (po)) or subcutaneously (s.c.). Positive control animals were dosed at 10 mg/kg daily with T enanthate. LA muscle was used as the indicator of efficacy with % efficacy (treated vs. vehicle-treated castrated animals) for (59) and (60) of 186% (s.c.) and 164% (po) at 10 mg/kg per day, respectively. Although no data was disclosed, these compounds reportedly did not increase weights of SV or prostate. The most active compounds are highly similar in structure. Apparently, p-CN, m-Cl, o-Me substitution of the A-ring (similar to BMS-564929 (29)) with an aryl R substituent off an otherwise unsubstituted pyrrolidine produces the most potent in vitro agonists, some of which also have in vivo agonist activity in LA. Pfizer has also reported SARM activity with a similar molecule ((62) in Figure 9), an N-arylpiperidine described supra. Likewise, GlaxoSmithKline has also reported similar compounds such as (55) with reported in vitro agonist activity [Trump et al., 2007] (Figure 8).


Selective androgen receptor modulators in preclinical and clinical development.

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

SARMs patented by Lilly, Pfizer, and Acadia.Lilly patented two SARM templates, the N-arylpyrrolidines and tetrahydrocarbazoles, which they characterize as tissue-selective.  Unfortunately, their comparisons are to vehicle-treated animals, making it hard to assess the relative activity compared to other templates.  Pfizer likewise has patented an aniline series of SARMs, which they characterize as high affinity and tissue-selective full agonists.  Acadia too has patented a novel SARM template of [3.2.1] tricyclic anilines, which they characterize as weak anabolic agents that suppress LH at therapeutic doses.
© Copyright Policy
Related In: Results  -  Collection

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

fig9: SARMs patented by Lilly, Pfizer, and Acadia.Lilly patented two SARM templates, the N-arylpyrrolidines and tetrahydrocarbazoles, which they characterize as tissue-selective. Unfortunately, their comparisons are to vehicle-treated animals, making it hard to assess the relative activity compared to other templates. Pfizer likewise has patented an aniline series of SARMs, which they characterize as high affinity and tissue-selective full agonists. Acadia too has patented a novel SARM template of [3.2.1] tricyclic anilines, which they characterize as weak anabolic agents that suppress LH at therapeutic doses.
Mentions: Substituted N-arylpyrrolidines: Lilly scientists patented a series of substituted N-arylpyrrolidines as a SARM template (World patent application WO2006 124447 [Gavardinas et al., 2006]). In vitro activity was reported for numerous compounds to achieve low nM AR binding with several potent transcriptional activators that approach full agonist efficacy in C2C12 cells as an indicator of agonist activity in muscle tissue. The in vivo activity was reported for two compounds (59) (reportedly commercially available) and (60), which were tested in castrated (at 8 weeks) mice after 8 weeks of wasting (Figure 9). Test animals were dosed over a two week timeframe at 0.3, 1, 3, 10, and 30 mg/kg per day by mouth (i.e., per os (po)) or subcutaneously (s.c.). Positive control animals were dosed at 10 mg/kg daily with T enanthate. LA muscle was used as the indicator of efficacy with % efficacy (treated vs. vehicle-treated castrated animals) for (59) and (60) of 186% (s.c.) and 164% (po) at 10 mg/kg per day, respectively. Although no data was disclosed, these compounds reportedly did not increase weights of SV or prostate. The most active compounds are highly similar in structure. Apparently, p-CN, m-Cl, o-Me substitution of the A-ring (similar to BMS-564929 (29)) with an aryl R substituent off an otherwise unsubstituted pyrrolidine produces the most potent in vitro agonists, some of which also have in vivo agonist activity in LA. Pfizer has also reported SARM activity with a similar molecule ((62) in Figure 9), an N-arylpiperidine described supra. Likewise, GlaxoSmithKline has also reported similar compounds such as (55) with reported in vitro agonist activity [Trump et al., 2007] (Figure 8).

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