Peripheral site acetylcholinesterase inhibitors targeting both inflammation and cholinergic dysfunction

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.

Graphical abstractThe design and synthesis of dual-action anti-inflammatory and anticholinergic agents are reported. Several of the compounds studied noncompetitively inhibit acetylcholinesterase (AChE) in the submicromolar range and release a pharmacologically active NSAID upon hydrolysis.Figure optionsDownload full-size imageDownload as PowerPoint slide