Design and synthesis of 1-heteroaryl-3-(1-benzyl-4-piperidinyl)propan-1-one derivatives as potent, selective acetylcholinesterase inhibitors.

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Nagel AA, Liston DR, Jung S, Mahar M, Vincent LA, Chapin D, Chen YL, Hubbard S, Ives JL, Jones SB, et al.

Design and synthesis of 1-heteroaryl-3-(1-benzyl-4-piperidinyl)propan-1-one derivatives as potent, selective acetylcholinesterase inhibitors.

J Med Chem. 1995 Mar 31;38(7):1084-9.

PubMed ID
7707311 [ View in PubMed
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Abstract

Herein is described the synthesis and structure--activity relationship of a novel series of aromatic and heteroaromatic 3-(1-benzyl-4-piperidinyl)propan-1-one derivatives that display potent and selective inhibition of the enzyme acetylcholinesterase (AChE). 1-(2-Methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)propan-1-one hydrochloride, 6d, is one of the most active compounds within this series exhibiting an IC50 for the inhibition of the AChE enzyme equal to 6.8 nM. Compound 6d has shown a dose-dependent elevation of total acetylcholine (ACh) levels in the mouse forebrain with an oral ED50 = 9.8 mg/kg. In addition, in vivo microdialysis experiments in the rat demonstrate that 6d increases extracellular ACh (100% over basal) 1-3 h postdose with an oral ED50 = 4.8 mg/kg.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DonepezilAcetylcholinesteraseIC 50 (nM)8N/AN/ADetails
PhysostigmineAcetylcholinesteraseIC 50 (nM)19N/AN/ADetails
TacrineAcetylcholinesteraseIC 50 (nM)267N/AN/ADetails