Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction

Bioorg Med Chem Lett. 2013 Mar 15;23(6):1891-5. doi: 10.1016/j.bmcl.2012.12.055. Epub 2013 Jan 8.

Abstract

We previously identified the methylsulfonylnitrobenzoates (MSNBs) that block the interaction of the thyroid hormone receptor with its obligate transcriptional coactivators and prevent thyroid hormone signaling. As part of our lead optimization work we demonstrated that sulfonylnitrophenylthiazoles (SNPTs), which replace the ester linkage of MSNBs with a thiazole, also inhibited coactivator binding to TR. Here we report that replacement of the ester with an amide (methylsulfonylnitrobenzamides, MSNBA) also provides active TR antagonists.

Publication types

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

MeSH terms

  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / toxicity
  • Cell Survival / drug effects
  • Hep G2 Cells
  • Humans
  • Nuclear Receptor Coactivator 1 / antagonists & inhibitors*
  • Nuclear Receptor Coactivator 1 / genetics
  • Nuclear Receptor Coactivator 1 / metabolism
  • Protein Interaction Maps / drug effects
  • Receptors, Thyroid Hormone / antagonists & inhibitors*
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Transfection

Substances

  • Benzamides
  • Receptors, Thyroid Hormone
  • Thiazoles
  • Nuclear Receptor Coactivator 1