Retinobenzoic acids. 6. Retinoid antagonists with a heterocyclic ring

J Med Chem. 1994 May 13;37(10):1508-17. doi: 10.1021/jm00036a017.

Abstract

Several candidate retinoid antagonists were designed on the basis of the ligand superfamily concept and synthesized. Retinoidal activities of these benzimidazole and benzodiazepine derivatives were examined by assay of differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. The parent benzimidazole derivative, 4-(5,6,7,8-tetrahydro-5,5,8,8- tetramethylnaphth-[2,3-d]imidazol-2-yl)benzoic acid (7a), and related compounds with a small alkyl group instead of the hydrogen on the nitrogen (1N) atom of the imidazole ring exhibited retinoidal activity, and the potency strongly depended on the bulkiness of the substituent. The compounds having a phenyl or benzyl group on the nitrogen lacked differentiation-inducing activity on HL-60 cells and acted as antagonists to the potent retinoid 4-[(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (Am80). Among the compounds possessing a seven-membered heterocyclic ring as a linking group, 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10- pentamethylbenzo[e]- naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid (16) also exhibited the antagonistic activity. The binding abilities of these compounds to retinoic acid receptors alpha and beta were consistent with their potency for the inhibition of HL-60 cell differentiation induced by the retinoid Am80.

MeSH terms

  • Benzimidazoles / pharmacology
  • Benzoates / antagonists & inhibitors
  • Benzoates / chemical synthesis
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Benzodiazepines / pharmacology
  • Cell Differentiation / drug effects
  • Cell Line
  • Drug Design
  • Humans
  • Receptors, Retinoic Acid / metabolism
  • Retinoids / antagonists & inhibitors*
  • Retinoids / chemical synthesis
  • Retinoids / chemistry
  • Retinoids / pharmacology*
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / antagonists & inhibitors
  • Tumor Cells, Cultured

Substances

  • Benzimidazoles
  • Benzoates
  • Receptors, Retinoic Acid
  • Retinoids
  • Tetrahydronaphthalenes
  • tamibarotene
  • Benzodiazepines