In neurodegenerative tauopathies, of which the most prevalent example is Alzheimer's disease, the aggregation of the microtubule (MT)-associated protein tau is believed to have neuropathological consequences that result from toxic gains and/or losses of normal tau functions. MT-stabilizing drugs can compensate for the loss of MT-stabilizing tau function in tauopathy neurons and, therefore, these molecules have been suggested as potential candidates to treat tau-mediated neurodegeneration. Epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tauopathy animal models, and this compound is presently undergoing testing in Phase 1b clinical trials. Epothilone D, however, exhibits potential deficiencies as a drug candidate, including an intravenous route of administration, the inhibition of the P-glycoprotein (Pgp) transporter, and a relatively complex/expensive synthesis. As a result, synthetically accessible, orally-active, brain-penetrant MT-stabilizing agents that do not interfere with Pgp function would be desirable. Towards this objective, our evaluation of different classes of known small-molecule MT-stabilizing agents led to the identification of selected triazolopyrimidines and phenylpyrimidines with these desired features. Pharmacodynamic studies confirmed that representative compounds produce MT-stabilization in the brain of mice, indicating that these synthetic small molecules may be promising leads to further develop as candidates for the treatment of tauopathies.

Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules as potential candidates for the treatment of Alzheimer's disease and related tauopathies

247th National Meeting (2014)

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