Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment

J Med Chem. 2002 Jul 18;45(15):3310-20. doi: 10.1021/jm0201013.


Recent efforts have focused on the design and synthesis of thyroid hormone (T(3)) antagonists as potential therapeutic agents and chemical probes to understand hormone-signaling pathways. We previously reported the development of novel first-generation T(3) antagonists DIBRT, HY-4, and GC-14 using the "extension hypothesis" as a general guideline in hormone antagonist design.(1-3) These compounds contain extensions at the 5'-position (DIBRT, GC-14) of the outer thyronine ring or from the bridging carbon (HY-4). All of these compounds have only a modest affinity and potency for the thyroid hormone receptor (TR) that limits studies of their antagonistic actions. Here, we report the design and synthesis of a novel series of 5'-phenylethynyl derivatives sharing the GC-1 halogen-free thyronine scaffold.(4) One compound (NH-3) is a T(3) antagonist with negligible TR agonist activity and improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions. NH-3 will be a useful pharmacological tool for further study of T(3) signaling and TR function.

Publication types

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

MeSH terms

  • Acetates / chemical synthesis*
  • Acetates / chemistry
  • Acetates / pharmacology
  • Binding, Competitive
  • DNA-Binding Proteins / agonists
  • DNA-Binding Proteins / metabolism
  • Drug Design
  • HeLa Cells
  • Humans
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Coactivator 2
  • Phenoxyacetates
  • Radioligand Assay
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Thyroid Hormone / agonists
  • Receptors, Thyroid Hormone / metabolism
  • Repressor Proteins / metabolism
  • Structure-Activity Relationship
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Triiodothyronine / antagonists & inhibitors*


  • (4-(4-hydroxy-3-isopropyl-5-(4-nitrophenylethynyl)benzyl)-3,5-dimethylphenoxy)acetic acid
  • Acetates
  • DNA-Binding Proteins
  • NCOR1 protein, human
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Coactivator 2
  • Phenoxyacetates
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Thyroid Hormone
  • Repressor Proteins
  • Transcription Factors
  • Triiodothyronine