posted on 2006-11-02, 00:00authored bySilke Dollinger, Stefan Löber, Ralf Klingenstein, Carsten Korth, Peter Gmeiner
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.