The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease

• Type of Material: Article
• Authors: Chun Chen, Emory University; Zhihao Wang, Emory University; Zhentao Zhang, Emory University; Xia Liu, Emory University; Seong Su Kang, Emory University; Ying Zhang, Emory University; Keqiang Ye, Emory University
• Language: English
• Date: 2018-01-16
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2018 National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1718683115
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 115
• Issue: 3
• Start Page: 578
• End Page: 583
• Grant/Funding Information: This work was supported by a grant from the National Institutes of Health (R01 DC010204, to K.Y.) and a grant from the National Natural Science Foundation of China (81771382, to Z.Z.).
• Keywords: TRANSGENIC MICE; Alzheimer's disease; prodrug; COGNITIVE DEFICITS; 7,8-dihydroxyflavone; BRAIN; BETA; pharmacokinetics; Multidisciplinary Sciences; BDNF; TRKB AGONIST; MEMORY DEFICITS; MOUSE MODEL; NEUROTROPHIC FACTOR; Science & Technology - Other Topics; TrkB; Science & Technology; PREVENTS SYNAPTIC LOSS
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

The BDNF mimetic compound 7,8-dihydroxyflavone (7,8-DHF), a potent small molecular TrkB agonist, displays prominent therapeutic efficacy against Alzheimer's disease (AD). However, 7,8-DHF has only modest oral bioavailability and a moderate pharmacokinetic (PK) profile. To alleviate these preclinical obstacles, we used a prodrug strategy for elevating 7,8-DHF oral bioavailability and brain exposure, and found that the optimal prodrug R13 has favorable properties and dose-dependently reverses the cognitive defects in an AD mouse model. We synthesized a large number of 7,8-DHF derivatives via ester or carbamate group modification on the catechol ring in the parent compound. Using in vitro absorption, distribution, metabolism, and excretion assays, combined with in vivo PK studies, we identified a prodrug, R13, that prominently up-regulates 7,8-DHF PK profiles. Chronic oral administration of R13 activated TrkB signaling and prevented Aβ deposition in 5XFAD AD mice, inhibiting the pathological cleavage of APP and Tau by AEP. Moreover, R13 inhibited the loss of hippocampal synapses and ameliorated memory deficits in a dose-dependent manner. These results suggest that the prodrug R13 is an optimal therapeutic agent for treating AD.