Thyroid Receptor Ligands. Part 4: 4'-amido Bioisosteric Ligands Selective for the Thyroid Hormone Receptor Beta

Bioorg Med Chem Lett. 2006 Feb 15;16(4):884-6. doi: 10.1016/j.bmcl.2005.11.002. Epub 2005 Nov 21.

Abstract

Based on the examination of the X-ray crystallographic structures of the LBD of TRalpha and TRbeta in complex with KB-141 (2), a number of novel 4'-hydroxy bioisosteric thyromimetics were prepared. Optimal affinity and beta-selectivity (33 times), was found with a medium-sized alkyl-substituted amido group; iso-butyl (12c). It can be concluded that bioisosteric replacements of the 4'-hydroxy position represent a new promising class of TRbeta-selective synthetic thyromimetics.

Publication types

  • Comparative Study

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Phenyl Ethers / chemistry
  • Phenylacetates / chemistry
  • Protein Conformation
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Thyroid Hormone Receptors alpha / drug effects
  • Thyroid Hormone Receptors beta / drug effects*
  • Thyroid Hormones / chemistry
  • Triiodothyronine / chemistry

Substances

  • Amides
  • KB 141
  • Ligands
  • Phenyl Ethers
  • Phenylacetates
  • Thyroid Hormone Receptors alpha
  • Thyroid Hormone Receptors beta
  • Thyroid Hormones
  • Triiodothyronine