Structure−Activity Relationship of Cyanine Tau Aggregation Inhibitors

Abstract

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.

Aminothienopyridazines and Methylene Blue Affect Tau Fibrillization via Cysteine Oxidation

“…Arguably, the most well known Tau fibrillization inhibitor is MB, which is undergoing evaluation in clinical trials as a therapy for AD (25). MB has been shown to inhibit 4-R Tau fibrillization (41)(42)(43) and is also known to be capable of redox cycling (44,45). We examined whether MB might behave like the ATPZs and induce the formation of a compact monomer of K18PL.…”

Structural Determinants of Tau Aggregation Inhibitor Potency

“…Nonetheless, small-molecule Tau aggregation inhibitors have been reported in the literature (5)(6)(7)(8)(9)(10). These consist of various chemotypes, including but not limited to phenothiazines (6), polyphenols (7), porphyrins (7), rhodanines (8), and cyanines (9,10), with phenothiazine derivative methylene blue showing promise for delaying progression of AD (11).…”

“…These consist of various chemotypes, including but not limited to phenothiazines (6), polyphenols (7), porphyrins (7), rhodanines (8), and cyanines (9,10), with phenothiazine derivative methylene blue showing promise for delaying progression of AD (11). Each scaffold family differs in molecular weight, hydrophobicity, and sterics, yet all inhibit Tau aggregation in vitro at micromolar or even submicromolar concentrations.…”

“…The problem is significant because most inhibitors identified to date on the basis of in vitro approaches have physical-chemical characteristics inconsistent with efficient blood-brain barrier penetration, hindering their preclinical evaluation. For example, thiacarbocyanine, phenothiazine, and arylmethine inhibitors are permanent cations (6,10,12), whereas porphyrin and pthalocyanine derivatives have relatively high molecular masses (7). Unlike these molecules, aggregation antagonists with improved bioavailability could have therapeutic utility.…”

Tau aggregation inhibitors: the future of Alzheimer’s pharmacotherapy?

“…[12] This value appears to be in the range of the in vitro IC 50 values for dissolution of PHFs (0.16 μM) and the calculated intracellular Ki for TAI activity (0.12 μM), [16] but not in the range of IC 50 s of other in vitro [5] and cell-based [17] studies. In tau transgenic mouse models, MT levels in the brain followed a sigmoidal concentration-response relationship over a 10-fold range (0.13-1.38 μM) after oral administration of 5-75 mg/kg for 3-8 weeks.…”