title: Design and synthesis of 1-heteroaryl-3-(1-benzyl-4-piperidinyl)propan-1-one derivatives as potent, selective acetylcholinesterase inhibitors.
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.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Nagel
authors.forename: D R
authors.initials: DR
authors.lastname: Liston
authors.forename: S
authors.initials: S
authors.lastname: Jung
authors.forename: M
authors.initials: M
authors.lastname: Mahar
authors.forename: L A
authors.initials: LA
authors.lastname: Vincent
authors.forename: D
authors.initials: D
authors.lastname: Chapin
authors.forename: Y L
authors.initials: YL
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Hubbard
authors.forename: J L
authors.initials: JL
authors.lastname: Ives
authors.forename: S B
authors.initials: SB
authors.lastname: Jones
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis*; D003342:Corpus Striatum / Q000378:metabolism; D015195:Drug Design; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D002800:Cholinesterase Inhibitors; D013844:Thiazoles; C092964:1-(2-methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)propan-1-one; D002091:Butyrylcholinesterase