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

Abstract 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‐ α ‐Akebonoic acid, which emanated from a high throughput screening ( HTS ), was discovered to interfere with PS1 / BACE1 interaction and reduce amyloid β‐protein (Aβ) 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 Aβ generation effectively.