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).

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Wagner CE, Jurutka PW, Marshall PA, Groy TL, van der Vaart A, Ziller JW, Furmick JK, Graeber ME, Matro E, Miguel BV, Tran IT, Kwon J, Tedeschi JN, Moosavi S, Danishyar A, Philp JS, Khamees RO, Jackson JN, Grupe DK, Badshah SL, Hart JW

J Med Chem. 2009 Oct 8;52(19):5950-66. doi: 10.1021/jm900496b.

PubMed ID

19791803 [ View in PubMed

]

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 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 EC(50) values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Bexarotene	Retinoic acid receptor RXR-alpha	Ki (nM)	21	N/A	N/A	Details
Bexarotene	Retinoic acid receptor RXR-alpha	EC 50 (nM)	52	N/A	N/A	Details