Donepezil-derived dual BuChE/FAAH inhibitors for multi-target Alzheimer's therapy
- Donepezil-based derivatives were designed and made as dual inhibitors of human butyrylcholinesterase and fatty acid amide hydrolase.
- Lead G15 inhibited both enzymes in a balanced way, with sub-micromolar to low-micromolar activity.
- It showed measurable selectivity over the carboxylesterases CES1 and CES2, a common liability for serine-hydrolase inhibitors.
💡 Points
Dual-target hybrids rarely land balanced potency on both enzymes, so G15 is a useful starting point. Selectivity over carboxylesterases is only modest, though, and I'd want in vivo exposure data before believing the multi-target rationale.