A Chimeric Ligand Approach Leading to Potent Antiprion Active Acridine Derivatives:  Design, Synthesis, and Biological Investigations

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 phar...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-11, Vol.49 (22), p.6591-6595
Main Authors: Dollinger, Silke, Löber, Stefan, Klingenstein, Ralf, Korth, Carsten, Gmeiner, Peter
Format: Article
Language:English
Subjects:
Acridines - chemical synthesis
Acridines - pharmacology
Animals
Biological and medical sciences
Blotting, Western
Cell Line, Tumor
Densitometry
Drug Design
Imipramine - analogs & derivatives
Imipramine - chemical synthesis
Imipramine - pharmacology
Indicators and Reagents
Ligands
Medical sciences
Mice
Miscellaneous
Neuropharmacology
Pharmacology. Drug treatments
Prions - drug effects
PrPSc Proteins - chemistry
PrPSc Proteins - drug effects
PrPSc Proteins - genetics
Quinacrine - analogs & derivatives
Quinacrine - chemical synthesis
Quinacrine - pharmacology
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060773j