The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity

The enzymatic activity
of butyrylcholinesterase (BChE) in the brain
increases with the progression of Alzheimer’s disease, thus
classifying BChE as a promising drug target in advanced Alzheimer’s
disease. We used structure-based drug discovery approaches to develop
potent, selective, and reversible human BChE inhibitors. The most
potent, compound 3, had a picomolar inhibition constant
versus BChE due to strong cation−π interactions, as revealed
by the solved crystal structure of its complex with human BChE. Additionally,
compound 3 inhibits BChE ex vivo and is noncytotoxic.
In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable.
Finally, compound 3 crosses the blood–brain barrier,
and it improves memory, cognitive functions, and learning abilities
of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of
drugs for alleviating symptoms of cholinergic hypofunction in patients
with advanced Alzheimer’s disease.