Dollinger Silke, Löber Stefan, Klingenstein Ralf, Korth Carsten, Gmeiner Peter
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
J Med Chem. 2006 Nov 2;49(22):6591-5. doi: 10.1021/jm060773j.
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 EC(50) value of 20 nM determined with a cell model of prion disease, thus substantially improving the antiprion efficacy of quinacrine.
包括克雅氏病在内的人类可传播性神经退行性疾病很独特，因为它们是由朊病毒引起的，朊病毒是一种传染性病原体，其复制无需核酸，而是通过诱导宿主细胞内正常朊病毒蛋白转变为错误折叠的构象异构体来实现。对于这些特殊疾病的药物治疗，人们曾考虑使用三环杂环化合物如奎纳克林，但迄今为止，其在体内的疗效尚不明确。基于奎纳克林和亚氨基二苄基衍生物的协同抗朊病毒作用，我们推出了一类新型潜在药物，它们是奎纳克林和丙咪嗪类似物的结构嵌合体。我们描述了这些化合物的聚焦文库的化学合成及生物活性测定。最有效的目标化合物2a在朊病毒病细胞模型中测得的半数有效浓度（EC50）值为20 nM，从而显著提高了奎纳克林的抗朊病毒效力。
