The BDNF mimetic compound 7,8-dihydroxyflavone (7,8-DHF), a potent small molecular TrkB agonist, displays prominent therapeutic efficacy against Alzheimer’s disease. However, 7,8-DHF has only modest oral bioavailability and a moderate pharmacokinetic profile. To alleviate these preclinical obstacles, the authors 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 Alzheimer’s mouse model. Chronic oral administration of R13 activated TrkB signaling and prevented Aβ deposition in Alzheimer model mice. Moreover, R13 inhibited the loss of hippocampal synapses and ameliorated memory deficits in a dose-dependent manner. The authors suggest that the prodrug R13 is a promising new therapeutic agent for treating Alzheimer’s Disease.
Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y and Ye K: The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease. Proc. Natl. Acad. Sci. USA [Epub ahead of print, January 2, 2018; doi:10.1073/pnas.1718683115].