NOVEL [2-(4-PIPERIDINYL)ETHYL](THIO)UREAS - SYNTHESIS AND ANTIACETYLCHOLINESTERASE ACTIVITY

被引:39
作者
VIDALUC, JL [1 ]
CALMEL, F [1 ]
BIGG, D [1 ]
CARILLA, E [1 ]
STENGER, A [1 ]
CHOPIN, P [1 ]
BRILEY, M [1 ]
机构
[1] CTR RECH PIERRE FABRE MEDICAMENT, DIV NEUROBIOL, F-81106 CASTRES, FRANCE
关键词
D O I
10.1021/jm00031a019
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 1-ar(o)yl-3- [2-(1-benzyl-4-piperidinyl)ethyl] (thio)urea derivatives was synthesized and evaluated for antiacetylcholinesterase activity. Most aroyl(thio)urea derivatives showed potent inhibitory activity in the sub-micromolar range. A comparable potency was obtained with the aryl(thio)urea analogues by replacing the phenyl with a 2-pyridylgroup. The substituted guanidine variations proved to be almost inactive whereas the nitroethylene analogues appeared to be quite efficient. These results were interpreted in terms of the preferential cis-trans conformation of the aroyl(thio) urea and 2-pyridyl(thio)urea moieties involving the existence of hydrogen bonding. In vivo experiments showed that compound 7m had maximal antiamnestic activity at 0.03 mg/kg with a therapeutic ratio greater than 1000, while cholinergic side effects were only seen at doses 100-fold the maximally effective antiamnestic dose. Compound 7m represents a potentially interesting antidementia agent.
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页码:689 / 695
页数:7
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