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)

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 lym...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 52; no. 19; pp. 5950 - 5966
Main Authors:	Wagner, Carl E, Jurutka, Peter W, Marshall, Pamela A, Groy, Thomas L, van der Vaart, Arjan, Ziller, Joseph W, Furmick, Julie K, Graeber, Mark E, Matro, Erik, Miguel, Belinda V, Tran, Ivy T, Kwon, Jungeun, Tedeschi, Jamie N, Moosavi, Shahram, Danishyar, Amina, Philp, Joshua S, Khamees, Reina O, Jackson, Jevon N, Grupe, Darci K, Badshah, Syed L, Hart, Justin W
Format:	Journal Article
Language:	English
Published:	Columbus, OH American Chemical Society 08-10-2009
Subjects:	Antineoplastic agents Apoptosis - drug effects Biological and medical sciences Cell Line, Tumor General aspects Humans Medical sciences Pharmacology. Drug treatments Retinoid X Receptors - agonists Structure-Activity Relationship Tetrahydronaphthalenes - chemical synthesis Tetrahydronaphthalenes - pharmacology Transcription, Genetic - drug effects Antineoplastic agent Agonist Bexarotene Toxicity Cytotoxicity Selectivity Mutagen Naphthalene derivatives In vitro Modeling Biological activity Benzoic acid derivatives Cell death Molecular model RXR retinoid receptor Fluorine Organic compounds Chemical synthesis Apoptosis
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Summary:	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 for RXR 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 K i 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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm900496b