A novel type of retinoic acid receptor antagonist: synthesis and structure-activity relationships of heterocyclic ring-containing benzoic acid derivatives

J Med Chem. 1995 Aug 4;38(16):3163-73. doi: 10.1021/jm00016a020.


A new series of heterocyclic ring-containing benzoic acids was prepared, and the binding affinity and antagonism of its members against all-trans-retinoic acid were evaluated by in vitro assay systems using human promyelocytic leukemia (HL-60) cells. Structure-activity relationships indicated that both an N-substituted pyrrole or pyrazole (1-position) and a hydrophobic region, with these linked by a ring system, were indispensable for effective antagonism. Among the compounds evaluated, optimal antagonism was exhibited by 4-[4,5,7,8,9,10-hexahydro-7,7,10,-10-tetramethyl-1-(3- pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoic acid (31), 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)-5- thiaanthral[1,2-b]pyrrol-3-yl]benzoic acid (40), and 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3- pyridylmethyl)anthra[2,1-d]pyrazol-3-yl]benzoic acid (55), all of which possess a 3-pyridylmethyl group at the five-membered ring nitrogen atom.

MeSH terms

  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • CD11 Antigens / metabolism
  • Cell Differentiation / drug effects
  • Drug Design
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • In Vitro Techniques
  • Receptors, Retinoic Acid / antagonists & inhibitors*
  • Receptors, Retinoic Acid / metabolism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Benzoates
  • CD11 Antigens
  • Heterocyclic Compounds
  • Receptors, Retinoic Acid