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) and (E)‑3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic Acid (CD3254)

Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 56; no. 21; pp. 8432 - 8454
Main Authors:	Jurutka, Peter W, Kaneko, Ichiro, Yang, Joanna, Bhogal, Jaskaran S, Swierski, Johnathon C, Tabacaru, Christa R, Montano, Luis A, Huynh, Chanh C, Jama, Rabia A, Mahelona, Ryan D, Sarnowski, Joseph T, Marcus, Lisa M, Quezada, Alexis, Lemming, Brittney, Tedesco, Maria A, Fischer, Audra J, Mohamed, Said A, Ziller, Joseph W, Ma, Ning, Gray, Geoffrey M, van der Vaart, Arjan, Marshall, Pamela A, Wagner, Carl E
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 14-11-2013
Subjects:	Coumaric Acids - chemical synthesis Coumaric Acids - chemistry Coumaric Acids - pharmacology Crystallography, X-Ray Dose-Response Relationship, Drug Humans Models, Molecular Molecular Structure Retinoid X Receptors - agonists Structure-Activity Relationship Tetrahydronaphthalenes - chemical synthesis Tetrahydronaphthalenes - chemistry Tetrahydronaphthalenes - pharmacology
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Summary:	Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.
Bibliography:	These authors contributed equally to this work.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm4008517