期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 14, 页码 6116-6127出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5005623
关键词
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资金
- NIH/NIA [AG044332-01]
- Comprehensive Neuroscience Center Pilot Grant (University of Pennsylvania)
- Marian S. Ware Alzheimer Program
- NSF [CHE-0840438]
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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