Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease.

Butyrylcholinesterase (BChE) is a viable drug target to alleviate the symptoms of Alzheimer's disease (AD). We recently developed and biologically evaluated racemic N-benzylpiperidine-based naphthalene-2-sulfonamide 2, a nanomolar BChE inhibitor with procognitive effects. To optimize it, we performed a chiral switch. Using semi-preparative chiral HPLC, we isolated the pure enantiomers (R)-(-)-2 and (S)-(+)-2 and confirmed that (R)-(-)-2 is the eutomer and (S)-(+)-2 is the distomer with respect to human (h)BChE inhibition. Notably, (R)-(-)-2 is a less potent inhibitor of human acetylcholinesterase (hAChE) than both racemate 2 and (S)-(+)-2, which is advantageous, since AChE inhibition is associated with undesirable peripheral parasympathomimetic adverse effects. The crystal structures of hBChE in complexes with each enantiomer revealed distinct binding poses. The crystal structure of hBChE in complex with (R)-(-)-2 confirmed our previous hypothesis that only the (R)-(-)-2 is bound in the active site of hBChE when the racemate is crystallized. The synthesis of (R)-2 hydrochloride has a higher overall yield (73 %) than the synthesis of racemate 2 hydrochloride (64 %) and is safer as it avoids the use of LiAlH4. (R)-(-)-2 has in vivo efficacy in mice with scopolamine-induced AD-like symptoms, and (R)-(-)-2 is less toxic in mice (LD50 = 169 mg/kg) than racemate 2 (LD50 = 112 mg/kg). These results support the chiral switch from racemate 2 to (R)-(-)-2 as a safer and more selective lead compound in the anti-AD drug development pipeline.