Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer's disease and related tauopathies.
Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer's disease and related tauopathies.
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DOI：
10.1021/jm5005623
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发表时间：
2014-07-24
影响因子：
7.3
通讯作者：
Ballatore C
中科院分区：
文献类型：
--
作者：
Lou K;Yao Y;Hoye AT;James MJ;Cornec AS;Hyde E;Gay B;Lee VM;Trojanowski JQ;Smith AB 3rd;Brunden KR;Ballatore C
微管 (MT) 稳定药物有望成为阿尔茨海默病 (AD) 和相关 tau蛋白病的潜在治疗方法。然而，迄今为止，埃坡霉素 D 是唯一在 tau 转基因小鼠和 AD 患者中进行评估的脑渗透性 MT 稳定剂。此外，这种天然产物作为候选药物表现出潜在的缺陷，包括静脉给药途径和抑制 P-糖蛋白 (Pgp) 转运蛋白。因此，寻找缺乏这些潜在限制的替代 CNS 活性 MT 稳定剂是很有意义的。为了实现这一目标，我们评估了已知类别的非天然存在的 MT 稳定小分子中的代表性化合物。这导致了选定的三唑并嘧啶和苯基嘧啶的鉴定，它们具有口服生物利用度和脑渗透性，且不破坏 Pgp 功能。药效学研究证实，这些系列的代表性化合物可增强野生型小鼠大脑中 MT 的稳定性。因此，这些类别的 MT 稳定剂有望开发口服活性、中枢神经系统导向的 MT 稳定疗法。
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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DOI：
10.1073/pnas.0406361102
发表时间：
2005-01-04
影响因子：
11.1
作者：
Zhang, B;Maiti, A;Trojanowski, JQ
通讯作者：
Trojanowski, JQ
影响因子：
3.5
作者：
Lamberth, Clemens;Trah, Stephan;Schneiter, Peter
通讯作者：
Schneiter, Peter
影响因子：
4.2
作者：
Yang, Wan Seok;Shimada, Kenichi;Delva, Darnelle;Patel, Milesh;Ode, Egberamwen;Skouta, Rachid;Stockwell, Brent R.
通讯作者：
Stockwell, Brent R.
影响因子：
5.3
作者：
Barten, Donna M.;Fanara, Patrizia;Albright, Charles F.
通讯作者：
Albright, Charles F.
影响因子：
4.2
作者：
Brunden, Kurt R.;Gardner, Nicola M.;Smith, Amos B., III
通讯作者：
Smith, Amos B., III