Modeling, Synthesis and Biological Evaluation of Potential RetinoidX Receptor-Selective Agonists: Novel Halogenated Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene)

Julie K. Furmick, Ichiro Kaneko, Angela N. Walsh, Joanna Yang, Jaskaran S. Bhogal, Geoffrey M. Gray, Juan C. Baso, Drew O. Browder, Jessica L S Prentice, Luis A. Montano, Chanh C. Huynh, Lisa M. Marcus, Dorian G. Tsosie, Jungeun S. Kwon, Alexis Quezada, Nicole M. Reyes, Brittney Lemming, Puneet Saini, Arjan vanderVaart, Thomas L. GroyPamela Marshall, Peter Jurutka, Carl Wagner

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

The synthesis of halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), known commonly as bexarotene, and their evaluation for retinoidX receptor (RXR)-specific agonist performance is described. Compound 1 is FDA approved to treat cutaneous T-cell lymphoma (CTCL); however, bexarotene treatment can induce hypothyroidism and elevated triglyceride levels, presumably by disrupting RXR heterodimer pathways for other nuclear receptors. The novel halogenated analogues in this study were modeled and assessed for their ability to bind to RXR and stimulate RXR homodimerization in an RXRE-mediated transcriptional assay as well as an RXR mammalian-2-hybrid assay. In an array of eight novel compounds, four analogues were discovered to promote RXR-mediated transcription with EC50 values similar to that of 1 and are selective RXR agonists. Our approach also uncovered a periodic trend of increased binding and homodimerization of RXR when substituting a halogen atom for a proton ortho to the carboxylic acid on 1.

Original languageEnglish (US)
Pages (from-to)1551-1566
Number of pages16
JournalChemMedChem
Volume7
Issue number9
DOIs
StatePublished - Sep 2012

Keywords

  • Bexarotene
  • Cutaneous T-cell lymphomas
  • Retinoic acid receptors
  • RetinoidX receptors
  • Rexinoids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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    Furmick, J. K., Kaneko, I., Walsh, A. N., Yang, J., Bhogal, J. S., Gray, G. M., Baso, J. C., Browder, D. O., Prentice, J. L. S., Montano, L. A., Huynh, C. C., Marcus, L. M., Tsosie, D. G., Kwon, J. S., Quezada, A., Reyes, N. M., Lemming, B., Saini, P., vanderVaart, A., ... Wagner, C. (2012). Modeling, Synthesis and Biological Evaluation of Potential RetinoidX Receptor-Selective Agonists: Novel Halogenated Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene). ChemMedChem, 7(9), 1551-1566. https://doi.org/10.1002/cmdc.201200319