A chimeric ligand approach leading to potent antiprion active acridine derivatives:: Design, synthesis, and biological investigations

被引:61
作者
Dollinger, Silke
Loeber, Stefan
Klingenstein, Ralf
Korth, Carsten
Gmeiner, Peter
机构
[1] Univ Erlangen Nurnberg, Emil Fischer Ctr, Dept Med Chem, D-91052 Erlangen, Germany
[2] Univ Dusseldorf, Sch Med, Inst Neuropathol, D-40225 Dusseldorf, Germany
关键词
D O I
10.1021/jm060773j
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Human transmissible neurodegenerations including Creutzfeldt-Jakob disease are unique, since they are caused by prions, an infectious agent that replicates without nucleic acids but instead by inducing conversion of a host-resident normal prion protein to a misfolded conformational isoform. For pharmacotherapy of these unusual diseases, tricyclic heterocyclic compounds such as quinacrine have been considered, but with ambiguous success in vivo, so far. On the basis of the synergistic antiprion effects of quinacrine and iminodibenzyl derivatives, we introduce a novel class of potential pharmaceuticals representing structural chimeras of quinacrine and imipramine analogues. We describe the chemical synthesis and bioassays of a focused library of these compounds. The most potent target compound 2a revealed an EC50 value of 20 nM determined with a cell model of prion disease, thus substantially improving the antiprion efficacy of quinacrine.
引用
收藏
页码:6591 / 6595
页数:5
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