A guanidine-appended scyllo-inositol derivative AAD-66 enhances brain delivery and ameliorates Alzheimer’s phenotypes

Alzheimer’s disease (AD) is a degenerative brain disease that destroys memory and other important mental functions but lacks efficient therapeutic agents. Blocking toxic amyloid β (Aβ) could be beneficial for AD and represents a promising therapeutic strategy for AD treatment. scyllo-Inositol (SI) is a potential therapeutic for AD by directly interacting with the Aβ peptide to inhibit Aβ42 fiber formation. Clinical studies of SI showed promising benefits on mild to moderate AD, however, with limitations on dosage regime. A new strategy to enhance the brain delivery of SI is needed to achieve the efficacy with minimum adverse effects. Herein, we report that a novel guanidine-appended SI derivative AAD-66 resulted in more effective reductions of brain Aβ and plaque deposits, gliosis, and behavioral memory deficits in the disease-established 5xFAD mice. Overall, our present study reveals the potential of AAD-66 as a promising therapeutic agent for AD.

. Body weight change during single dose toxicity test.
8 weeks old ICR mice (each n=5) were administered 1,000mpk of AAD-66 on day0. Body weight was measured on dya1, 3, 7, and 14. ( 1 H-NMR at 500MHz; 13 C-NMR at 125MHz) spectrometers. Tetramethysilane was used as reference, and the chemical shift were reported in ppm and the coupling constant in Hz.
Low resolution mass spectra were determined on a Micromass PLATFORM ll (EI and FAB).
High resolution mass spectra were obtained on JMS-700 or MALDI TOF mass spectra on a Voyager-DE STR system at the Korea Basic Science Support Center. The standard extractive work-up procedure consisted of pouring into a large amount of water, extracting thoroughly with the organic solvent indicated, washing the combined extract successively with water and brine, drying the extract over anhydrous Na 2 SO 4 or MgSO 4 , and evaporating the solvent.
The present reaction was also carried out in a different solvent system of MeOH: CH 2 Cl 2 (4: 1) to afford a similar yield.