Evaluation of the Structure-Activity Relationship of Microtubule-Targeting 1,2,4-Triazolo[1,5-a]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies.
Evaluation of the Structure-Activity Relationship of Microtubule-Targeting 1,2,4-Triazolo[1,5-a]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies.
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DOI：
10.1021/acs.jmedchem.0c01605
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发表时间：
2021-01-28
影响因子：
7.3
通讯作者：
Ballatore C
中科院分区：
文献类型：
--
作者：
Oukoloff K;Nzou G;Varricchio C;Lucero B;Alle T;Kovalevich J;Monti L;Cornec AS;Yao Y;James MJ;Trojanowski JQ;Lee VM;Smith AB 3rd;Brancale A;Brunden KR;Ballatore C
对 tau 蛋白和 Aβ 斑块转基因小鼠模型的研究表明，大脑渗透性微管 (MT) 稳定化合物，包括 1,2,4-三唑并[1,5-a]嘧啶，有望成为阿尔茨海默病 (AD) 和相关神经退行性 tau 病的候选治疗方法。三唑并嘧啶已被研究作为抗癌药物；然而，这些化合物的抗有丝分裂活性并不总是与细胞中 MT 的稳定性相关。事实上，我们实验室之前的研究发现，C6 连接的片段在确定三唑并嘧啶是否促进 MT 稳定或相反破坏细胞中 MT 完整性方面发挥着关键作用。为了进一步阐明构效关系 (SAR) 并确定神经退行性疾病的潜在改良 MT 稳定候选物，设计、合成和评估了一套全面的 68 个在 C6 和/或 C7 处具有结构修饰的三唑并嘧啶同系物。这些研究扩展了对三唑并嘧啶 SAR 的先前了解，并能够鉴定出新型类似物，这些类似物相对于现有的先导药物，表现出改进的理化性质、MT 稳定活性和药代动力学。
Studies in tau and Aβ plaque transgenic mouse models demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the 1,2,4-triazolo[1,5-a]pyrimidines, hold promise as candidate treatments for Alzheimer’s disease (AD) and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anti-cancer agents; however, the anti-mitotic activity of these compounds does not always correlate with stabilization of MTs in cells. Indeed, previous studies from our laboratories identified a critical role for the fragment linked at C6 in determining whether triazolopyrimidines promote MT stabilization or, conversely, disrupt MT integrity in cells. To further elucidate the structure-activity relationship (SAR) and to identify potentially improved MT-stabilizing candidates for neurodegenerative disease, a comprehensive set of 68 triazolopyrimidine congeners bearing structural modifications at C6 and/or C7 was designed, synthesized and evaluated. These studies expand upon prior understanding of triazolopyrimidine SAR and enabled the identification of novel analogues that, relative to the existing lead, exhibit improved physicochemical properties, MT-stabilizing activity and pharmacokinetics.
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影响因子：
7.3
作者：
Fleming FF;Yao L;Ravikumar PC;Funk L;Shook BC
通讯作者：
Shook BC
影响因子：
12.7
作者：
Sadleir KR;Kandalepas PC;Buggia-Prévot V;Nicholson DA;Thinakaran G;Vassar R
通讯作者：
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影响因子：
7.3
作者：
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通讯作者：
Bajorath, Juergen
影响因子：
5.6
作者：
Sander, Thomas;Freyss, Joel;Rufener, Christian
通讯作者：
Rufener, Christian
DOI：
10.1016/b978-0-12-409547-2.12353-4
发表时间：
2017-01-01
期刊：
COMPREHENSIVE MEDICINAL CHEMISTRY III, VOL 3: IN SILICO DRUG DISCOVERY TOOLS
影响因子：
--
作者：
Tosco, P.;Mackey, M.
通讯作者：
Mackey, M.