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This version published online on September 28, 2006
Endocrinology, doi:10.1210/en.2006-0843
A more recent version of this article appeared on January 1, 2007
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Submitted on June 21, 2006
Accepted on September 19, 2006

Pharmacological and X-ray Structural Characterization of a Novel Selective Androgen Receptor Modulator: Potent Hyperanabolic Stimulation of Skeletal Muscle with Hypostimulation of Prostate in Rats

Jacek Ostrowski, Joyce E. Kuhns, John A. Lupisella, Mark C. Manfredi, Blake C. Beehler, Stanley R. Krystek Jr, Yingzhi Bi*, Chongqing Sun, Ramakrishna Seethala, Rajasree Golla, Paul G. Sleph, Aberra Fura, Yongmi An, Kevin F. Kish, John S. Sack, Kasim A. Mookhtiar*, Gary J. Grover*, and Lawrence G. Hamann*

Departments of Metabolic Diseases, Discovery Chemistry, Macromolecular Structure, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ 08543, USA

* To whom correspondence should be addressed. E-mail: ybi{at}lexpharma.com or kasim.mookhtiar{at}advinus.com or garygrover{at}productsafetylabs.com or lawrence.hamann{at}bms.com.

A novel, highly potent, orally active, non-steroidal tissue selective androgen receptor modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar androgen receptor agonist in vitro, is highly selective for the androgen receptor vs. other steroid hormone receptors, and exhibits no significant interactions with sex hormone binding globulin or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone in stimulating the growth of the levator ani muscle, and unlike testosterone, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the androgen receptor relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. As concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks which limit testosterone's clinical use, the potent oral activity and tissue selectivity exhibited by BMS-564929 is expected to yield a clinical profile which provides the demonstrated beneficial effects of testosterone in muscle and other tissues with a more favorable safety window.
Key words: Androgen Receptor • Tissue Selectivity • SARM • Anabolic Agent




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