Department of Medicinal Chemistry, Mylan School of Pharmacy, Duquesne University, 600 Forbes Hall, Pittsburgh, PA 15282, USA.
Bioorg Med Chem. 2011 Jan 1;19(1):359-73. doi: 10.1016/j.bmc.2010.11.022. Epub 2010 Dec 6.
Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive and behavioral impairment. The two classic pathological hallmarks of AD include extraneuronal deposition of amyloid β (Aβ) and intraneuronal formation of neurofibrillary tangles (NFTs). NFTs contain hyperphosphorylated tau. Tau is the major microtubule-associated protein in neurons and stabilizes microtubules (MTs). Cyclin dependent kinase 5 (CDK5), when activated by the regulatory binding protein p25, phosphorylates tau at a number of proline-directed serine/threonine residues, resulting in formation of phosphorylated tau as paired helical filaments (PHFs) then in subsequent deposition of PHFs as NFTs. Beginning with the structure of Roscovitine, a moderately selective CDK5 inhibitor, we sought to conduct structural modifications to increase inhibitory potency of CDK5 and increase selectivity over a similar enzyme, cyclin dependent kinase 2 (CDK2). The design, synthesis, and testing of a series of 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles is presented.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，导致认知和行为障碍。AD 的两个经典病理学特征包括细胞外淀粉样β（Aβ）沉积和细胞内神经原纤维缠结（NFT）形成。NFT 含有过度磷酸化的 tau。Tau 是神经元中主要的微管相关蛋白，可稳定微管（MTs）。周期蛋白依赖性激酶 5（CDK5）在调节结合蛋白 p25 的激活下，在许多脯氨酸定向丝氨酸/苏氨酸残基处磷酸化 tau，导致磷酸化 tau 形成双螺旋丝（PHFs），然后进一步沉积为 NFT。从 Roscovitine 的结构开始，一种中度选择性的 CDK5 抑制剂，我们试图进行结构修饰以提高 CDK5 的抑制效力，并提高对类似酶，细胞周期蛋白依赖性激酶 2（CDK2）的选择性。呈现了一系列 1-异丙基-4-氨基苄基-6-醚连接的苯并咪唑的设计、合成和测试。
