Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities transla...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-05, Vol.285 (22), p.17054-17064
Main Authors: Schmidt, Azriel, Kimmel, Donald B., Bai, Chang, Scafonas, Angela, Rutledge, SuJane, Vogel, Robert L., McElwee-Witmer, Sheila, Chen, Fang, Nantermet, Pascale V., Kasparcova, Viera, Leu, Chih-tai, Zhang, Hai-Zhuan, Duggan, Mark E., Gentile, Michael A., Hodor, Paul, Pennypacker, Brenda, Masarachia, Patricia, Opas, Evan E., Adamski, Sharon A., Cusick, Tara E., Wang, Jiabing, Mitchell, Helen J., Kim, Yuntae, Prueksaritanont, Thomayant, Perkins, James J., Meissner, Robert S., Hartman, George D., Freedman, Leonard P., Harada, Shun-ichi, Ray, William J.
Format: Article
Language:English
Subjects:
Androgen
Androgens - metabolism
Animals
Azasteroids - chemistry
Azasteroids - pharmacology
Bone Formation
Cell Line, Tumor
Chemistry, Pharmaceutical - methods
Chlorocebus aethiops
COS Cells
Drug Action
Drug Design
Female
Gene Regulation
Hormone Antagonists - pharmacology
Hormones
Humans
Ligands
Male
Models, Biological
Nuclear Receptors
Protein Structure, Tertiary
Rats
Receptors, Androgen - chemistry
Receptors, Cytoplasmic and Nuclear - metabolism
Sarcopenia
Steroid Hormone
Steroid Hormone Receptor
Steroids - metabolism
Transcription Regulation
Transcription, Genetic
Transcriptional Activation
Virilization
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Summary:Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40–80% of an agonist, recruited the coactivator GRIP-1
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.099002