In Alzheimer’s disease and related neurodegenerative tauopathies, the aggregation of the microtubule (MT)-associated protein tau is believed to have neuropathological consequences that result from toxic gains and/or losses of tau functions. Different MT-stabilizing natural products, including selected taxanes, epothilone D and dictyostatin, have been found effective in animal models of neurodegenerative tauopathies due to their ability to compensate for MT deficits presumed to result from the loss of tau MT-stabilizing function in neurons. Among non-naturally occurring MT-stabilizing compounds, the triazolopyrimidines comprise a promising class that is characterized by generally favorable drug-like properties, including brain-penetration and oral bioavailability. At the molecular level, however, such molecules have been found to act on MTs in a substantially different manner compared to typical MT-stabilizing natural products. To investigate the potential of this class of compounds in the context of neurodegenerative tauopathies, structure-activity relationship (SAR) studies resulted in the identification of a prototype triazolopyrimidine congener, CNDR-51657, with suitable PK/PD properties.  Evaluation of this compound in aged (9-month-old) PS19 tau transgenic mice that harbor neurofibrillary tangle (NFT)-like tau pathology in the CNS revealed that low doses (3 or 10 mg/Kg) twice-weekly for 3 months produce improvements in neuronal outcomes that resemble those previously observed upon treatment with MT-stabilizing natural products. Moreover, mice treated with either dose of CNDR-51657 did not show signs of compound intolerance during treatment. These results further confirm that stabilization of axonal MTs may be a promising strategy to treat neurodegenerative tauopathies and suggest that triazolopyrimidines hold considerable promise as CNS-active MT-stabilizing candidate therapeutics.

Evaluation of triazolopyrimidine microtubule-stabilizing small molecules as potential candidates for the treatment of Alzheimer’s disease and related tauopathies

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.