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

Anja Schäfer, Ethan S Burstein, Roger Olsson

Journal: Bioorganic & medicinal chemistry letters 2014;24(8):1944-7

PMID: 24666648

Full Text on Elsevier Science View on PubMed

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.

Address: 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.; 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: [email protected].

DOI: 10.1016/j.bmcl.2014.03.003

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MeSH Terms: Bexarotene, Drug Delivery Systems, Indolequinones, Indoles, Molecular Structure, NAD(P)H Dehydrogenase (Quinone), Prodrugs, Retinoid X Receptors, Tetrahydronaphthalenes