Pharmacophore-based design and discovery of (−)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis

摘要

Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer’s disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (−)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate >43 was highly potent (IC50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, >43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. >43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ42) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP695 cells at 50 µM. The dual actions of >43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.