title: Bexarotene prodrugs: targeting through cleavage by NQO1 (DT-diaphorase).
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.
authors.affiliation: Department of Chemistry and Molecular Biology/Medicinal Chemistry, University of Gothenburg, SE-412 96 Gothenburg, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: ACADIA Pharmaceuticals Inc., 11085 Torreyanna Road, Suite 100, San Diego, CA 92121, USA.
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
authors.affiliation: 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.
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
mesh_terms: D000077610:Bexarotene; D016503:Drug Delivery Systems; D045563:Indolequinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047488:Retinoid X Receptors / Q000819:agonists; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D045563:Indolequinones; D007211:Indoles; D011355:Prodrugs; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; C000592455:bexarotene-3-(hydroxymethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione ester; D000077610:Bexarotene; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Alzheimer’s disease; Bexarotene; Disease targeting; Parkinson’s disease; Prodrugs; dt diaphorase