Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids

J Med Chem. 1994 Sep 2;37(18):2930-41. doi: 10.1021/jm00044a014.


Two series of potent retinoid X receptor (RXR)-selective compounds were designed and synthesized based upon recent observation that (E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1- propenyl]benzoic acid (TTNBP) binds and transactivates only the retinoic acid receptor (RAR) subtypes whereas (E)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydro-2-naphthalenyl)-1-propenyl]benzoic acid (3-methyl TTNPB) binds and transactivates both the RAR and RXR subfamilies. Addition of functional groups such as methyl, chloro, bromo, or ethyl to the 3 position of the tetrahydronaphthalene moiety of 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid (5a) and 4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (6a) results in compounds which elicit potent and selective activation of the RXR class. Such RXR-selective compounds offer pharmacological tools for elucidating the biological role of the individual retinoid receptors with which they interact. Activation profiles in cotransfection and competitive binding assays as well as molecular modeling calculations demonstrate critical structural determinants that confer selectivity for members of the RXR subfamily. The most potent compound of these series, 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]ben zoi c acid (6b), is the first RXR-selective retinoid (designated as LGD1069) to enter clinical trials for cancer indications.

MeSH terms

  • Benzoates / chemical synthesis
  • Benzoates / pharmacology
  • Binding, Competitive
  • Gene Expression Regulation / drug effects
  • Models, Molecular
  • Molecular Conformation
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Retinoic Acid / drug effects
  • Retinoid X Receptors
  • Retinoids / chemical synthesis*
  • Retinoids / metabolism
  • Retinoids / pharmacology
  • Structure-Activity Relationship
  • Transcription Factors*
  • Transfection


  • Benzoates
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Retinoids
  • Transcription Factors
  • 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid