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. 2010 May 1;20(9):2987-90.
doi: 10.1016/j.bmcl.2010.02.102. Epub 2010 Mar 3.

Peripheral site acetylcholinesterase inhibitors targeting both inflammation and cholinergic dysfunction

Sherri Young  1 , Karine Fabio, Christophe Guillon, Pramod Mohanta, Timothy A Halton, Diane E Heck, Robert A Flowers 2nd, Jeffrey D Laskin, Ned D Heindel
Affiliations

Peripheral site acetylcholinesterase inhibitors targeting both inflammation and cholinergic dysfunction

Sherri Young et al. Bioorg Med Chem Lett. .

Abstract

The design and study of two classes of noncompetitive acetylcholinesterase inhibitors (AChEIs) which also function as NSAID prodrugs are reported. The most potent AChEIs disclosed contain an aromatic alkyl-aryl linker between an NSAID and a lipophilic choline mimic and they inhibit acetylcholinesterase (AChE) in the submicromolar range. These agents have the therapeutic potential to dually target inflammation by releasing an NSAID in vivo and activating the cholinergic anti-inflammatory pathway via cholinergic up-regulation.

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Figures

Figure 1
Figure 1
Generic Structures of Class 1 (top) and Class 2 (bottom) agents.
Figure 2
Figure 2
Structure of 7, the most potent AChEI discussed herein (IC50 = 0.51 μM).
Scheme 1
Scheme 1
Synthesis of Class 1 agents. a) Et3N, THF, −10 to 25°C; b) NSAID, EDC HCl, DMAP, CH2Cl2, 0 to 25°C.
See this image and copyright information in PMC

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