Development of proneurogenic, neuroprotective small molecules.
Development of proneurogenic, neuroprotective small molecules.
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DOI：
10.1021/ja108211m
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发表时间：
2011-02-09
影响因子：
15
通讯作者：
Ready JM
中科院分区：
文献类型：
--
作者：
MacMillan KS;Naidoo J;Liang J;Melito L;Williams NS;Morlock L;Huntington PJ;Estill SJ;Longgood J;Becker GL;McKnight SL;Pieper AA;De Brabander JK;Ready JM
海马体的退化与阿尔茨海默病有关，并且在疾病进展的非常早期发生。目前治疗与阿尔茨海默氏症相关的认知症状的选择是不够的，迫切需要寻找新的治疗策略。安全地增强海马神经发生的药物可能提供新的治疗方法。我们发现了第一个合成分子，命名为P7C3，它可以保护新生神经元免于凋亡细胞死亡，从而促进小鼠和大鼠海马齿状回颗粒下区的神经发生，这是成年哺乳动物正常神经发生的部位。我们描述了药物化学活动的结果，以优化P7C3的效力、毒性特征和稳定性。铅化合物的几乎每一个位置的系统变化揭示了有利于增加活性的元素和受修饰的区域。我们已经发现了可口服的、无毒的、在小鼠、大鼠和细胞培养物中稳定的并且能够穿透血脑屏障的化合物。最有效的化合物在纳摩尔浓度下具有活性。最后，我们已经确定了衍生物，可以通过亲和层析或光交联促进作用模式的研究。
Degeneration of the hippocampus is associated with Alzheimer’s disease, and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer’s are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apopotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive towards increases in activity and regions subject to modification. We have discovered compounds that are orally available, non-toxic, stable in mice, rats and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photocrosslinking.
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影响因子：
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作者：
Eriksson, PS;Perfilieva, E;Gage, FH
通讯作者：
Gage, FH
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