Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions

J Med Chem. 2002 Aug 1;45(16):3327-30. doi: 10.1021/jm0255320.

Abstract

Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Naphthylamine / analogs & derivatives*
  • 2-Naphthylamine / chemical synthesis
  • 2-Naphthylamine / chemistry
  • 2-Naphthylamine / pharmacology
  • Benzoates / pharmacology
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology
  • Cell Differentiation / drug effects
  • Depression, Chemical
  • Dimerization
  • HL-60 Cells
  • Humans
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Receptors, Retinoic Acid / antagonists & inhibitors*
  • Retinoid X Receptors
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / pharmacology
  • Transcription Factors / antagonists & inhibitors*

Substances

  • Benzoates
  • Carboxylic Acids
  • PA024 compound
  • Pyrimidines
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Tetrahydronaphthalenes
  • Transcription Factors
  • tamibarotene
  • 2-Naphthylamine