Synthetic Analogues of Betulinic Acid as Potent Inhibitors of PS1/BACE1 Interaction to Reduce Aβ Generation

The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer's disease (AD) treatment as an inhibitor of PS1/BACE1 interaction. 3--Akebonoic acid, which emanated from a high throughput screening (HTS), was discovered to interfere with PS1/BACE1 interaction and reduce amyloid -protein (A) production. In view of the limited source, we instead used naturally rich betulinic acid (compound 2) as starting material for lead optimization and a focused library of its derivatives was constructed to gain a better understanding of the structure activity relationship (SAR) of triterpenoid-type inhibitor of PS1/BACE1 interaction. Compound 22 was finally chosen as the most potent PS1/BACE1 interaction inhibitor, which reduced A generation effectively.