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

Casey E. Bohl, Zengru Wu, Jiyun Chen, Michael L. Mohler, Jun Yang, Dong Jin Hwang, Suni Mustafa, Duane D. Miller, Charles E. Bell, James T. Dalton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5567-5570
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number20
DOIs
Publication statusPublished - 15 Oct 2008
Externally publishedYes

Keywords

  • Androgen receptor
  • Cachexia
  • Crystallography
  • Prostate cancer
  • SARM

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