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 Aβ(1-42)-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.