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Modeling, Synthesis and Biological Evaluation of Potential Retinoid X 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)
Author(s) -
Furmick Julie K.,
Kaneko Ichiro,
Walsh Angela N.,
Yang Joanna,
Bhogal Jaskaran S.,
Gray Geoffrey M.,
Baso Juan C.,
Browder Drew O.,
Prentice Jessica L. S.,
Montano Luis A.,
Huynh Chanh C.,
Marcus Lisa M.,
Tsosie Dorian G.,
Kwon Jungeun S.,
Quezada Alexis,
Reyes Nicole M.,
Lemming Brittney,
Saini Puneet,
van der Vaart Arjan,
Groy Thomas L.,
Marshall Pamela A.,
Jurutka Peter W.,
Wagner Carl E.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200319
Subject(s) - bexarotene , retinoid x receptor , agonist , nuclear receptor , chemistry , retinoid , receptor , retinoid x receptor alpha , stereochemistry , retinoid x receptor beta , biochemistry , pharmacology , transcription factor , biology , retinoic acid , gene
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 retinoid X 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 EC 50 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 .