Bexarotene prodrugs: Targeting through cleavage by NQO1 (DT-diaphorase)

被引：14
|
作者：
Schafer, Anja [1 ]
Burstein, Ethan S. [2 ]
Olsson, Roger [1 ,2 ,3 ]
机构：
[1] Univ Gothenburg, Dept Chem & Mol Biol Med Chem, SE-41296 Gothenburg, Sweden
[2] ACADIA Pharmaceut Inc, San Diego, CA 92121 USA
[3] Lund Univ, Dept Expt Med Sci, SE-22184 Lund, Sweden
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 08期
关键词：
Prodrugs; Parkinson's disease; Alzheimer's disease; dt diaphorase; Disease targeting; Bexarotene; INDOLEQUINONE ANTITUMOR AGENTS; NAD(P)H-QUINONE OXIDOREDUCTASE; QUINONE STRUCTURE; METABOLISM; ACTIVATION; DOPAMINE; EXPRESSION; MECHANISM; DESIGN; ELIMINATION;
D O I：
10.1016/j.bmcl.2014.03.003
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Bexarotene, a retinoid X receptor (RXR) agonist, is being tested as a potential disease modifying treatment for neurodegenerative conditions. To limit the peripheral exposure of bexarotene and release it only in the affected areas of the brain, we designed a prodrug strategy based on the enzyme NAD( P) H/quinone oxidoreductase (NQO1) that is elevated in neurodegenerative diseases. A series of indolequinones (known substrates of NQO1) was synthesized and coupled to bexarotene. Bexarotene-3(hydroxymethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione ester 7a was cleaved best by NQO1. The prodrugs are not cleaved by esterase. (C) 2014 Elsevier Ltd. All rights reserved.
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页码：1944 / 1947
页数：4
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