Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
J Med Chem. 2021 Jan 28;64(2):1073-1102. doi: 10.1021/acs.jmedchem.0c01605. Epub 2021 Jan 7.
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-]pyrimidines, hold promise as candidate treatments for Alzheimer's disease and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anticancer agents; however, the antimitotic 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.
在 tau 和 Aβ 斑块转基因小鼠模型中的研究表明，穿透血脑屏障的微管（MT）稳定剂，包括 1,2,4-三唑并[1,5-a]嘧啶，有望成为治疗阿尔茨海默病和相关神经退行性 tau 病的候选药物。三唑嘧啶已被研究为抗癌药物；然而，这些化合物的抗有丝分裂活性并不总是与细胞中 MT 的稳定相关。事实上，我们实验室的先前研究确定了连接在 C6 上的片段在决定三唑嘧啶是否促进 MT 稳定或相反地破坏细胞中 MT 完整性方面的关键作用。为了进一步阐明结构-活性关系（SAR）并确定用于神经退行性疾病的潜在改良的 MT 稳定剂候选物，设计、合成和评估了一组包含在 C6 和/或 C7 处进行结构修饰的 68 种三唑嘧啶同系物。这些研究扩展了对三唑嘧啶 SAR 的先前理解，并能够鉴定出与现有先导化合物相比，具有改善的物理化学性质、MT 稳定活性和药代动力学的新型类似物。
