Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4411(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-yI)-4-hydroxyphenyl)acrylic Acid (CD3254)

被引：28

作者：

Jurutka, Peter W. ^{[1
]}

Kaneko, Ichiro ^{[1
]}

Yang, Joanna ^{[1
]}

Bhogal, Jaskaran S. ^{[1
]}

Swierski, Johnathon C. ^{[1
]}

Tabacaru, Christa R. ^{[1
]}

Montano, Luis A. ^{[1
]}

Huynh, Chanh C. ^{[1
]}

Jama, Rabia A. ^{[1
]}

Mahelona, Ryan D. ^{[1
]}

Sarnowski, Joseph T. ^{[1
]}

Marcus, Lisa M. ^{[1
]}

Quezada, Alexis ^{[1
]}

Lemming, Brittney ^{[1
]}

Tedesco, Maria A. ^{[1
]}

Fischer, Audra J. ^{[1
]}

Mohamed, Said A. ^{[1
]}

Ziler, Joseph W. ^{[2
]}

Ma, Ning ^{[3
]}

Gray, Geoffrey M. ^{[3
]}

van der Vaart, Arjan ^{[3
]}

Marshall, Pamela A. ^{[1
]}

Wagner, Carl E. ^{[1
]}

机构：

[1] Arizona State Univ, New Coll Interdisciplinary Arts & Sci, Sch Math & Nat Sci, Glendale, AZ 85306 USA

[2] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA

[3] Univ S Florida, Dept Chem, Tampa, FL 33620 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 21期

基金：

美国国家卫生研究院;

关键词：

VITAMIN-D-RECEPTOR; ENHANCES BASOLATERAL EFFLUX; THYROID-HORMONE RECEPTOR; 9-CIS-RETINOIC ACID; GROWTH-INHIBITION; CRYSTAL-STRUCTURE; PACLITAXEL TAXOL; DNA-BINDING; ACTIVATION; LIGANDS;

D O I：

10.1021/jm4008517

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Three unreported analogues of 44143,5,5,8,8pentamethyl-5-6-7-8-tetrahydro-2-naphthypethynyllbenzoic 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-y1)-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.

引用

页码：8432 / 8454

页数：23

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