Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy.
Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy.
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DOI：
10.1021/jm300353r
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发表时间：
2012-08-09
影响因子：
7.3
通讯作者：
Thatcher, Gregory R. J.
中科院分区：
文献类型：
--
作者：
Qjn, Zhihui;Luo, Jia;VandeVrede, Lawren;Tavassoli, Ehsan;Fa', Mauro;Teich, Andrew F.;Arancio, Ottavio;Thatcher, Gregory R. J.
阿尔茨海默病（AD）的学习和记忆缺陷是由突触失效和神经元损失引起的，后者部分由兴奋性毒性和氧化应激引起。描述了一种治疗方法，该方法使用NO-嵌合体来恢复突触功能和神经保护。4-甲基噻唑（MZ）衍生物的合成，基于一个领先的神经保护药效团的GABAA受体增强的一部分。测定MZ衍生物对原代神经元的氧-葡萄糖剥夺和兴奋性毒性的保护作用。选择的神经保护衍生物被纳入NO-嵌合体前药，创造诺美噻唑。为了提供诺美噻唑药物类别的概念证明，测定了所选实施例：AD转基因小鼠海马切片中突触功能的恢复;认知缺陷的逆转;以及前药及其神经保护性MZ代谢物的脑生物利用度。总之，测定数据表明，这些嵌合诺美噻唑可用于治疗神经退行性疾病如AD的多种组分。
Learning and memory deficits in Alzheimer’s disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described, which uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABAA receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for: restoration of synaptic function in hippocampal slices from AD-transgenic mice; reversal of cognitive deficits; and, brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD.
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