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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / antagonists & inhibitors
  • Amides / chemistry*
  • Cachexia / drug therapy
  • Chemistry, Pharmaceutical / methods*
  • Crystallography, X-Ray / methods
  • Drug Design
  • Humans
  • Ligands
  • Male
  • Models, Chemical
  • Molecular Conformation
  • Muscles / pathology
  • Osteoporosis / drug therapy
  • Protein Structure, Tertiary
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / metabolism*


  • Amides
  • Ligands
  • Receptors, Androgen
  • propionamide