Orally Bioavailable Prodrugs of ψ‑GSH: A Potential Treatment for Alzheimer’s Disease

Addressing glycation-induced oxidative stress in Alzheimer’s
disease (AD) is an emerging pharmacotherapeutic strategy. Restoration
of the brain glyoxalase enzyme system that neutralizes reactive dicarbonyls
is one such approach. Toward this end, we designed, synthesized, and
evaluated a γ-glutamyl transpeptidase-resistant glyoxalase substrate,
ψ-GSH. Although mechanistically successful, the oral efficacy
of ψ-GSH appeared as an area in need of improvement. Herein,
we describe our rationale for the creation of prodrugs that mask the
labile sulfhydryl group. In vitro and in
vivo stability studies identified promising prodrugs that
could deliver pharmacologically relevant brain levels of ψ-GSH.
When administered orally to a mouse model generated by the intracerebroventricular
injection of Aβ1–42, the compounds conferred cognitive
benefits. Biochemical and histological examination confirmed their
effects on neuroinflammation and oxidative stress. Collectively, we
have identified orally efficacious prodrugs of ψ-GSH that are
able to restore brain glyoxalase activity and mitigate inflammatory
and oxidative pathology associated with AD.