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), twenty-five 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.