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

Anja Schäfer; Ethan S Burstein; Roger Olsson

doi:10.1016/j.bmcl.2014.03.003

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

Bioorg Med Chem Lett. 2014 Apr 15;24(8):1944-7. doi: 10.1016/j.bmcl.2014.03.003. Epub 2014 Mar 13.

Authors

Anja Schäfer¹, Ethan S Burstein², Roger Olsson³

Affiliations

¹ Department of Chemistry and Molecular Biology/Medicinal Chemistry, University of Gothenburg, SE-412 96 Gothenburg, Sweden.
² ACADIA Pharmaceuticals Inc., 11085 Torreyanna Road, Suite 100, San Diego, CA 92121, USA.
³ Department of Chemistry and Molecular Biology/Medicinal Chemistry, University of Gothenburg, SE-412 96 Gothenburg, Sweden; ACADIA Pharmaceuticals Inc., 11085 Torreyanna Road, Suite 100, San Diego, CA 92121, USA; Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University, SE-221 84 Lund, Sweden. Electronic address: roger.olsson@med.lu.se.

PMID: 24666648
DOI: 10.1016/j.bmcl.2014.03.003

Abstract

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.

Keywords: Alzheimer’s disease; Bexarotene; Disease targeting; Parkinson’s disease; Prodrugs; dt diaphorase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bexarotene
Drug Delivery Systems*
Indolequinones / chemical synthesis
Indolequinones / chemistry
Indolequinones / pharmacology
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacology
Molecular Structure
NAD(P)H Dehydrogenase (Quinone) / chemistry*
Prodrugs / chemical synthesis*
Prodrugs / chemistry
Prodrugs / pharmacology
Retinoid X Receptors / agonists
Tetrahydronaphthalenes / chemical synthesis*
Tetrahydronaphthalenes / chemistry*
Tetrahydronaphthalenes / pharmacology

Substances

Indolequinones
Indoles
Prodrugs
Retinoid X Receptors
Tetrahydronaphthalenes
bexarotene-3-(hydroxymethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione ester
Bexarotene
NAD(P)H Dehydrogenase (Quinone)
NQO1 protein, human