SYNTHESES, RESOLUTION, AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF POTENT ACETYLCHOLINESTERASE INHIBITORS - 8-CARBAPHYSOSTIGMINE ANALOGS

被引:46
作者
CHEN, YPL [1 ]
NIELSEN, J [1 ]
HEDBERG, K [1 ]
DUNAISKIS, A [1 ]
JONES, S [1 ]
RUSSO, L [1 ]
JOHNSON, J [1 ]
IVES, J [1 ]
LISTON, D [1 ]
机构
[1] PFIZER INC,DIV CENT RES,DEPT NEUROSCI,GROTON,CT 06340
关键词
D O I
10.1021/jm00086a011
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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).
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页码:1429 / 1434
页数:6
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