title: 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H- pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: a potent and centrally-selective inhibitor of acetylcholinesterase with an improved margin of safety.
abstract: A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC50S = 0.33 - 3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC50S = 600 - 23,000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (> 10,000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED50 = 26 +/- 1.5 mg/kg) and acute lethality (LD50[1 h] = 42 mg/kg) were observed at > 60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Inc, Groton, Connecticut 06340, USA.
authors.forename: A
authors.initials: A
authors.lastname: Villalobos
authors.forename: T W
authors.initials: TW
authors.lastname: Butler
authors.forename: D S
authors.initials: DS
authors.lastname: Chapin
authors.forename: Y L
authors.initials: YL
authors.lastname: Chen
authors.forename: S B
authors.initials: SB
authors.lastname: DeMattos
authors.forename: J L
authors.initials: JL
authors.lastname: Ives
authors.forename: S B
authors.initials: SB
authors.lastname: Jones
authors.forename: D R
authors.initials: DR
authors.lastname: Liston
authors.forename: A A
authors.initials: AA
authors.lastname: Nagel
authors.forename: D M
authors.initials: DM
authors.lastname: Nason
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000494:pharmacology / Q000633:toxicity
chemical_list: C095054:5,7-dihydro-3-(2-(1-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2-f)-1,2-benzisoxazol-6-one; D002800:Cholinesterase Inhibitors; D007555:Isoxazoles; D010880:Piperidines; D013619:Tacrine; D002091:Butyrylcholinesterase