title: Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen.
abstract: Glucosyl derivates exhibited favorable distribution to the brain. However, bidirectional transport of glucose transporter 1 might decrease concentrations of the prodrugs in brain before the release of parent drugs. To overcome this defect, glucosyl thiamine disulfide prodrugs 1a-1c incorporating naproxen were designed and synthesized. Furthermore, prodrug 2 and 3 were also prepared as control. The favorable physicochemical properties of these prodrugs were verified by stability and metabolism studies. Results from the in vivo distribution study indicated that 1a-1c, and 1b in particular, significantly increased the level of naproxen in brain when compared to 2 and 3. The study suggested glucosyl thiamine disulfide was a promising carrier to enhance the brain bioavailability of central nervous system active drugs.
authors.affiliation: Key Laboratory of Drug Targeting of China Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.forename: Xian-Kun
authors.initials: XK
authors.lastname: Li
authors.forename: Nian
authors.initials: N
authors.lastname: Yao
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.forename: Yong-Guo
authors.initials: YG
authors.lastname: Yu
authors.forename: Li
authors.initials: L
authors.lastname: Hai
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004220:Disulfides / Q000737:chemistry*; D015195:Drug Design; D005960:Glucosides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D009288:Naproxen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004220:Disulfides; D005960:Glucosides; D011355:Prodrugs; D009288:Naproxen