Brain-Penetrant, Orally Bioavailable Microtubule-Stabilizing Small Molecules Are Potential Candidate Therapeutics for Alzheimer鈥檚 Disease and Related Tauopathies

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• 作者：Kevin Lou ; Yuemang Yao ; Adam T. Hoye ; Michael J. James ; Anne-Sophie Cornec ; Edward Hyde ; Bryant Gay ; Virginia M.-Y. Lee ; John Q. Trojanowski ; Amos B. Smith ; III ; Kurt R. Brunden ; Carlo Ballatore
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：6116-6127
• 全文大小：493K
• ISSN：1520-4804

文摘

Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer鈥檚 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.