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.

Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase/monoamine oxidase inhibitors for the potential application against Alzheimer’s disease

“…Activation of different carboxylic acid compounds with 1,1 0 -carbonyldiimidazole (CDI) and subsequent coupling to 1-benzylpiperidin-4-amine or 2-(1-benzylpiperidin-4-yl) ethanamine afforded target compounds w1-23 in good yields [46][47][48] . Structures of all synthesized compounds were characterized by 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy (see Supplementary data).…”

Donepezil Improves Cognition and Global Function in Alzheimer Disease<subtitle>A 15-Week, Double-blind, Placebo-Controlled Study</subtitle>

“…In contrast, no significant effect was seen for the placebo group. (8) 28 (18) .001 Diarrhea 4 (3) 10 (6) 21 (13) .001 Pain 11 (7) 14 (9) 21 (13) .20 Headache 13 (8) 21 (13) 19 (12) .37 Dizziness 10 (7) 14 (9) 14 (9) .69 Muscle cramp 6 (4) 9 (6) 12 (8 During the 12-week active treatment period, approximately 60% of patients receiving 10 mg/d of donepezil achieved a best change score of 4 points or more on the ADAS-cog, as opposed to approximately 30% of the placebo controls. An improvement of 4 or more points on the ADAS-cog is considered by regulatory authorities to be clinically meaningful.…”

Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor

“…On the basis of these findings, we synthesized benzamide derivatives. We later on discovered that benzylsulfonyl derivative (compound 4) was the most potent AChE inhibitor with an anti-AChE activity 21,000-fold greater compared to the seed compound (26,32,33) (Fig. 4).…”