The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold

被引:51
作者
Graczyk, PP
Khan, A
Bhatia, GS
Palmer, V
Medland, D
Numata, H
Oinuma, H
Catchick, J
Dunne, A
Ellis, M
Smales, C
Whitfield, J
Neame, SJ
Shah, B
Wilton, D
Morgan, L
Patel, T
Chung, R
Desmond, H
Staddon, JM
Sato, N
Inoue, A
机构
[1] UCL, Eisai London Res Labs, London WC1E 6BT, England
[2] Eisai & Co Ltd, Tsukuba Res Labs, Tsukuba, Ibaraki 3002635, Japan
关键词
D O I
10.1016/j.bmcl.2005.07.076
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Imidazole-based structures of p38 inhibitors served as a starting point for the design of JNK3 inhibitors. Construction of a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold led to the synthesis of the (S)-enantiomers, which exhibited p38/JNK3 IC50 ratio of up to 10 and were up to 20 times more potent inhibitors of JNK3 than the relevant (R)-enantiomers. The JNK3 inhibitory potency correlated well with inhibition of c-Jun phosphorylation and neuroprotective properties of the compounds in low K+-induced cell death of rat cerebellar granule neurotics. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:4666 / 4670
页数:5
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