Modeling, synthesis and biological evaluation of potential Retinoid X Receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene)

Carl Wagner, Peter Jurutka, Pamela Marshall, Thomas L. Groy, Arjan Van Der Vaart, Joseph W. Ziller, Julie K. Furmick, Mark E. Graeber, Erik Matro, Belinda V. Miguel, Ivy T. Tran, Jungeun Kwon, Jamie N. Tedeschi, Shahram Moosavi, Amina Danishyar, Joshua S. Philp, Reina O. Khamees, Jevon N. Jackson, Darci K. Grupe, Syed L. BadshahJustin W. Hart

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated forRXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.

Original languageEnglish (US)
Pages (from-to)5950-5966
Number of pages17
JournalJournal of Medicinal Chemistry
Volume52
Issue number19
DOIs
StatePublished - Oct 8 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Wagner, C., Jurutka, P., Marshall, P., Groy, T. L., Van Der Vaart, A., Ziller, J. W., Furmick, J. K., Graeber, M. E., Matro, E., Miguel, B. V., Tran, I. T., Kwon, J., Tedeschi, J. N., Moosavi, S., Danishyar, A., Philp, J. S., Khamees, R. O., Jackson, J. N., Grupe, D. K., ... Hart, J. W. (2009). Modeling, synthesis and biological evaluation of potential Retinoid X Receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene). Journal of Medicinal Chemistry, 52(19), 5950-5966. https://doi.org/10.1021/jm900496b