Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer’s Disease

Butyrylcholinesterase
(BChE) is a promising drug target for alleviating
the symptoms of canine cognitive dysfunction (CCD) and Alzheimer’s
disease (AD). We have recently developed lead compound 2, a racemic, nanomolar BChE inhibitor with procognitive effects in
mice with scopolamine-induced AD-like symptoms and dogs suffering
from CCD. To overcome its modest brain exposure, we developed compound (R)-(−)-3, a more potent
BChE inhibitor with a 7-fold higher in vivo brain exposure. It has
procognitive effects in mice with scopolamine-induced AD-like symptoms
and, superior to compound 2, also in mice with Aβ1–42-induced AD-like symptoms. Compound (R)-(−)-3 produces no cholinergic
adverse effects or motor deficits and has no acute toxic effects in
mice. This makes sulfonamide (R)-(−)-3 an optimized lead compound for alleviating
the symptoms of AD.