Discovery and Optimization of α‑Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia

To
validate PDE4 inhibitors as novel therapeutic agents against
vascular dementia (VaD), 25 derivatives were discovered from the natural
inhibitor α-mangostin (IC50 = 1.31 μM). Hit-to-lead
optimization identified a novel and selective PDE4 inhibitor 4e (IC50 = 17 nM), which adopted a different binding
pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration
of 4e at a dose of 10 mg/kg exhibited remarkable therapeutic
effects in a VaD model and did not cause emesis to beagle dogs, indicating
its potential as a novel anti-VaD agent.