Structure-guided Synthesis of Tamoxifen Analogs With Improved Selectivity for the Orphan ERRgamma

Bioorg Med Chem Lett. 2006 Feb 15;16(4):821-4. doi: 10.1016/j.bmcl.2005.11.030. Epub 2005 Nov 22.

Abstract

The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRgamma LBD confirms the molecular basis of the selectivity.

Publication types

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

MeSH terms

  • Binding Sites / drug effects
  • Crystallography, X-Ray
  • Drug Design
  • Estrogen Receptor alpha / drug effects
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Estrogen / drug effects*
  • Structure-Activity Relationship
  • Tamoxifen* / analogs & derivatives
  • Tamoxifen* / chemical synthesis
  • Tamoxifen* / pharmacology

Substances

  • ESRRG protein, human
  • Estrogen Receptor alpha
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Tamoxifen