Inclusions comprised of fibrils of the microtubule (MT)-associated protein tau are found in the brains of those with Alzheimer's disease (AD) and other neurodegenerative tauopathies. The pathology that is observed in these diseases is believed to result from the formation of toxic tau oligomers or fibrils, and/or from the loss of normal tau function due to its sequestration into insoluble deposits. Hence, small molecules that prevent tau oligomerization and/or fibrillization might have therapeutic value. Indeed, examples of such compounds have been published but nearly all have properties that render them unsuitable as drug candidates. For these reasons, we conducted quantitative high-throughput screening (qHTS) of ~292,000 compounds to identify drug-like inhibitors of tau assembly. The fibrillization of a truncated tau fragment that contains four MT-binding domains was monitored in an assay that employed complementary thioflavine T fluorescence and fluorescence polarization methods. Previously described classes of inhibitors as well as new scaffolds were identified, including novel aminothienopyridazines (ATPZ's). A number of ATPZ analogs were synthesized and structure-activity relationships were defined. Further characterization of representative ATPZ compounds showed they do not interfere with tau-mediated MT assembly, and they are significantly more effective at preventing the fibrillization of tau than the Aβ(1-42) peptide which forms AD senile plaques. Thus, the ATPZ molecules described here represent a novel class of tau assembly inhibitors that merit further development for testing in animal models of AD-like tau pathology.Intracellular accumulations comprised of hyper-phosphorylated forms of the protein tau are found within the somatodendritic regions of neurons in Alzheimer's disease (AD), certain frontotemporal dementias and a host of additional neurodegenerative disorders that are broadly referred to as "tauopathies" (for review see (1)). These tau lesions correlate with the severity of dementia in AD (2-4) and missense mutations within the tau gene lead to inherited forms of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) (5;6). † This work was supported by grants from the National Institutes of Health (P01 AG09215, P30 AG10124, P01 AG11542, P01 AG14382, Philadelphia, PA 19104-4283, Tel: (215) Fax: (215) 349-5909, kbrunden@mail.med.upenn.edu. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2010 August 18. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThus, tau has been directly implicated as a causative agent in AD and related neurodegenerative diseases.Normally, tau binds to tubulin and is believed to promote MT assembly and stabilization (7)(8)(9). This role of tau is particularly important in neurons, where the stability of MTs is critical for axonal transport and the delivery of cellular materials to and from synapses (10). Tau is normally phosphorylated and the extent of this post-tra...

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NCGC00229600, a small-molecule allosteric inverse agonist of TSHR, is a general antagonist of TSH receptor activation by TSAbs in GD patient sera.