title: Novel piperidine derivatives. Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives.
abstract: A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives was synthesized and evaluated for anti-acetylcholinesterase (anti-AChE) activity. Substituting the benzamide with a bulky moiety in the para position led to a substantial increase in activity. Introduction of an akyl or phenyl group at the nitrogen atom of benzamide dramatically enhanced the activity. The basic quality of the nitrogen atom of piperidine appears to play an important role in the increased activity, since the N-benzoylpiperidine derivative was almost inactive. We found that 1-benzyl-4-[2-(N-[4'-(benzylsulfonyl) benzoyl]-N-methylamino]ethyl]piperidine hydrochloride (21) (IC50 = 0.56 nM) is one of the most potent inhibitors of acetylcholinesterase. Compound 21 showed an affinity 18,000 times greater for AChE than for BuChE. At a dose of 3 mg/kg, 21 produced a marked and significant increase in acetylcholine (ACh) content in the cerebral vortex and hippocampus of rats. Compound 21 was chosen for advanced development as an antidementia agent.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: H
authors.initials: H
authors.lastname: Sugumi
authors.forename: K
authors.initials: K
authors.lastname: Higurashi
authors.forename: N
authors.initials: N
authors.lastname: Karibe
authors.forename: Y
authors.initials: Y
authors.lastname: Iimura
authors.forename: A
authors.initials: A
authors.lastname: Sasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: S
authors.initials: S
authors.lastname: Araki
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D010830:Physostigmine / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000494:pharmacology
chemical_list: D001593:Benzyl Compounds; D002800:Cholinesterase Inhibitors; D007202:Indicators and Reagents; D010880:Piperidines; C064766:1-benzyl-4-(2-(N-(4'-(benzylsulfonyl)benzoyl)-N-methylamino)ethyl)piperidine; D013619:Tacrine; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase