Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors

J Med Chem. 2009 Jul 9;52(13):3892-901. doi: 10.1021/jm9002704.


We have previously reported the discovery and preliminary structure activity relationships of a series of beta-aminoketones that disrupt the binding of coactivators to TR. However, the most active compounds had moderate inhibitory potency and relatively high cytotoxicity, resulting in narrow therapeutic index. Additionally, preliminary evaluation of in vivo toxicology revealed a significant dose related cardiotoxicity. Here we describe the improvement of pharmacological properties of thyroid hormone receptor coactivator binding inhibitors. A comprehensive survey of the effects of substitutents in key areas of the molecule was carried out based on mechanistic insight from the earlier report. This study revealed that both electron withdrawing and hydrophobic substituents on the aromatic ring led to higher potency. On the other hand, moving from an alkyl to a sulfonyl alkyl side chain led to reduced cytotoxicity. Finally, utilization of amine moieties having low pK(a)'s resulted in lowered ion channel activity without any loss of pharmacological activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines
  • Antithyroid Agents / adverse effects
  • Antithyroid Agents / chemistry*
  • Antithyroid Agents / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Ion Channels / chemistry
  • Ion Channels / metabolism
  • Ketones / chemical synthesis
  • Ketones / chemistry*
  • Ketones / pharmacology
  • Protein Binding / drug effects
  • Receptors, Thyroid Hormone / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Amines
  • Antithyroid Agents
  • Ion Channels
  • Ketones
  • Receptors, Thyroid Hormone