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Bioorg Med Chem Lett. 2008 Oct 15;18(20):5567-70. doi: 10.1016/j.bmcl.2008.09.002. Epub 2008 Sep 5.

Effect of B-ring substitution pattern on binding mode of propionamide selective androgen receptor modulators.

Author information

1
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, 242 L.M. Parks Hall, Columbus, OH 43210, USA.

Abstract

Selective androgen receptor modulators (SARMs) are essentially prostate sparing androgens, which provide therapeutic potential in osteoporosis, male hormone replacement, and muscle wasting. Herein we report crystal structures of the androgen receptor (AR) ligand-binding domain (LBD) complexed to a series of potent synthetic nonsteroidal SARMs with a substituted pendant arene referred to as the B-ring. We found that hydrophilic B-ring para-substituted analogs exhibit an additional region of hydrogen bonding not seen with steroidal compounds and that multiple halogen substitutions affect the B-ring conformation and aromatic interactions with Trp741. This information elucidates interactions important for high AR binding affinity and provides new insight for structure-based drug design.

PMID:
18805694
PMCID:
PMC2577784
DOI:
10.1016/j.bmcl.2008.09.002
[Indexed for MEDLINE]
Free PMC Article

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