Ring nitrogen-substituted non-steroidal estrogens: pyridine and pyrimidine analogs of the phenol in deoxyhexestrol experience resonance constraints on preferred ligand conformation

Bioorg Med Chem Lett. 2004 Dec 6;14(23):5835-9. doi: 10.1016/j.bmcl.2004.09.048.

Abstract

To develop compounds selective for estrogen receptor beta (ERbeta), we substituted hydroxypyridine and pyrimidine heteroaryl groups for the characteristic phenol ring of non-steroidal estrogens. The unexpectedly low affinity showed by some of these compounds is ascribed, in part, to a resonance-enforced conformational constraint that prevents their optimal accommodation in the ER ligand binding pocket.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Estrogens, Non-Steroidal / chemistry*
  • Estrogens, Non-Steroidal / metabolism
  • Humans
  • Ligands
  • Molecular Conformation
  • Phenols / chemistry*
  • Phenols / metabolism
  • Protein Binding / physiology
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism

Substances

  • Estrogens, Non-Steroidal
  • Ligands
  • Phenols
  • Pyridines
  • Pyrimidines