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

  • Author(s): Ballatore, C
  • Lou, K
  • Hoye, A
  • Gay, B
  • Cornec, A-S
  • James, MJ
  • Yao, Y
  • Hyde, E
  • Trojanowski, JQ
  • Lee, VM-Y
  • Smith, AB
  • Brunden, KR
  • et al.

Published Web Location

http://pubs.acs.org/doi/pdf/10.1021/jm5005623
No data is associated with this publication.
Abstract

Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer's disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administration and the inhibition of the P-glycoprotein (Pgp) transporter. Thus, the identification of alternative CNS-active MT-stabilizing agents that lack these potential limitations is of interest. Toward this objective, we have evaluated representative compounds from known classes of non-naturally occurring MT-stabilizing small molecules. This led to the identification of selected triazolopyrimidines and phenylpyrimidines that are orally bioavailable and brain-penetrant without disruption of Pgp function. Pharmacodynamic studies confirmed that representative compounds from these series enhance MT-stabilization in the brains of wild-type mice. Thus, these classes of MT-stabilizers hold promise for the development of orally active, CNS-directed MT-stabilizing therapies.

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