Syntheses, resolution, and structure-activity relationships of potent acetylcholinesterase inhibitors: 8-carbaphysostigmine analogues.
The synthesis of a series of 1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole 5-alkylcarbamates and their resolution are reported. These compounds are structurally related to physostigmine with substitution of a methylene group in place of the NMe group at position 8 of physostigmine. Many of these 8-carbaphysostigmine analogues are more potent acetylcholinesterase inhibitors in vitro and less toxic in vivo than physostigmine. The (-)-enantiomer (e.g., 1d and 1g) possessing the same absolute configuration at C3a and C8a as that of physostigmine, is about 6 to 12-fold more potent at inhibiting acetylcholinesterase than the corresponding (+)-enantiomer (e.g., 1e and 1h).
Chen
Y L
YL
Medicinal Chemistry Department, Pfizer Inc., Groton, Connecticut 06340.
Nielsen
J
J
Hedberg
K
K
Dunaiskis
A
A
Jones
S
S
Russo
L
L
Johnson
J
J
Ives
J
J
Liston
D
D
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D010830:Physostigmine