Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related derivatives.
Following the discovery of a new series of 1-benzyl-4-[2-(N-benzoyl-N-methylamino)ethyl]piperidine (2) derivatives with a potent anti-acetylcholinesterase (anti-AChE) activity, we extended the structure-activity relationships (SAR) to rigid analogues (4) and 1-benzyl-4-[2-(N-benzoyl-N-phenylamino)ethyl]piperidine derivatives (3). Introduction of a phenyl group on the nitrogen atom of the amide moieties resulted in enhanced activity. The rigid analogue containing isoindolone (9) was found to exhibit potent anti-AChE activity comparable to that of 2. Furthermore, replacement of the isoindolone with other heterobicyclic ring systems was examined. Among the compounds prepared in these series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE. Compound 19 showed a definite selectivity to AChE over the BuChE (about 34700-fold) and, at dosages of 10-50 mg/kg, exerted a dose-dependent inhibitory effect on AChE in rat brain.
Sugimoto
H
H
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Tsuchiya
Y
Y
Sugumi
H
H
Higurashi
K
K
Karibe
N
N
Iimura
Y
Y
Sasaki
A
A
Araki
S
S
Yamanishi
Y
Y
Yamatsu
K
K
D000110:Acetylcholinesterase; D000818:Animals; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D010797:Phthalimides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D010797:Phthalimides; D010880:Piperidines; C078818:1-benzyl-4-(2-(4-(benzoylamino)phthalimido)ethyl)piperidine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase