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

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.

SUBMITTER: Bohl CE

PROVIDER: S-EPMC2577784 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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

Bohl Casey E CE Wu Zengru Z Chen Jiyun J Mohler Michael L ML Yang Jun J Hwang Dong Jin DJ Mustafa Suni S Miller Duane D DD Bell Charles E CE Dalton James T JT

Bioorganic & medicinal chemistry letters 20080905 20

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 hydro ...[more]

PMID: 18805694

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