Structure−Activity Relationship of Cyanine Tau Aggregation Inhibitors

• Published in: Journal of medicinal chemistry Vol. 52; no. 11; pp. 3539 - 3547
• Main Authors: Chang, Edward, Congdon, Erin E, Honson, Nicolette S, Duff, Karen E, Kuret, Jeff
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 11.06.2009
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Carbocyanines - pharmacology; Medical sciences; Mice; Mice, Transgenic; Neuropharmacology; Organ Culture Techniques; Pharmacology. Drug treatments; Protein Structure, Quaternary - drug effects; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship; tau Proteins - drug effects; tau Proteins - metabolism; Chain length; Rodentia; Central nervous system; Molecular interaction; Polymethine dye; Serum albumin; Benzothiazole derivatives; Serum protein; In vitro; Cyanine dye; Encephalon; Aggregation; Vertebrata; Biological fixation; Mammalia; Tau protein; Structure activity relation; Mouse; Animal; Inhibitor; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900116d

A structure−activity relationship for symmetrical cyanine inhibitors of human tau aggregation was elaborated using a filter trap assay. Antagonist activity depended on cyanine heterocycle, polymethine bridge length, and the nature of meso- and N-substituents. One potent member of the series, 3,3′-diethyl-9-methylthiacarbocyanine iodide (compound 11), retained submicromolar potency and had calculated physical properties consistent with blood−brain barrier and cell membrane penetration. Exposure of organotypic slices prepared from JNPL3 transgenic mice (which express human tau harboring the aggregation prone P301L tauopathy mutation) to compound 11 for one week revealed a biphasic dose response relationship. Low nanomolar concentrations decreased insoluble tau aggregates to half those observed in slices treated with vehicle alone. In contrast, high concentrations (≥300 nM) augmented tau aggregation and produced abnormalities in tissue tubulin levels. These data suggest that certain symmetrical carbocyanine dyes can modulate tau aggregation in the slice biological model at concentrations well below those associated with toxicity.