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

Jinhao LiangYi-You HuangQian ZhouYuqi GaoZhe LiDeyan WuSi YuLei GuoZhen ChenLing HuangSteven H LiangXixin HeRuibo WuHai-Bin Luo
Published in: Journal of medicinal chemistry (2020)
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.
Keyphrases
  • mild cognitive impairment
  • cognitive impairment
  • small molecule
  • photodynamic therapy
  • high throughput
  • structure activity relationship
  • dna binding
  • single cell