Microtubule-Stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as Candidate Therapeutics for Neurodegenerative Disease: Matched Molecular Pair Analyses and Computational Studies Reveal New Structure-Activity Insights.
Microtubule-Stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as Candidate Therapeutics for Neurodegenerative Disease: Matched Molecular Pair Analyses and Computational Studies Reveal New Structure-Activity Insights.
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DOI：
10.1021/acs.jmedchem.2c01411
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发表时间：
2023-01-12
影响因子：
7.3
通讯作者：
Ballatore, Carlo
中科院分区：
文献类型：
--
作者：
Alle, Thibault;Varricchio, Carmine;Yao, Yuemang;Lucero, Bobby;Nzou, Goodwell;Demuro, Stefania;Muench, Megan;Vuong, Khoa D.;Oukoloff, Killian;Cornec, Anne-Sophie;Francisco, Karol R.;Caffrey, Conor R.;Lee, Virginia M. -Y.;Smith III, Amos B.;Brancale, Andrea;Brunden, Kurt R.;Ballatore, Carlo
微管（MT）稳定的1，2，4-三唑并[1，5-a]嘧啶（TPD）有望成为阿尔茨海默病（AD）和其他神经退行性疾病的候选治疗剂。然而，取决于TPD核心周围取代基的选择，这些化合物可以引发明显不同的细胞表型，其可能由TPD同源物与微管蛋白异二聚体内的一个或两个空间上不同的结合位点的相互作用引起（即，第七个站点和vinca站点）。在本研究中，我们报告了一系列新的TPD同系物的设计，合成和评价，以及匹配的分子对分析和计算研究，进一步阐明了MT活性TPD的构效关系。这些研究导致鉴定了新的MT标准化TPD候选物，其表现出有利的ADME-PK，包括脑渗透和口服生物利用度，以及脑药效学活性。
Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer’s disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure–activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity.
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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：
7.3
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
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DOI：
10.1002/alz.12144
发表时间：
2020-10
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
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影响因子：
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DOI：
10.1523/jneurosci.4922-11.2012
发表时间：
2012-03-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Zhang B;Carroll J;Trojanowski JQ;Yao Y;Iba M;Potuzak JS;Hogan AM;Xie SX;Ballatore C;Smith AB 3rd;Lee VM;Brunden KR
通讯作者：
Brunden KR