口服生物利用度 ψ-GSH 前药：阿尔茨海默病的潜在治疗方法。
Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer's Disease.
机构信息
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, United States.
出版信息
J Med Chem. 2022 Nov 10;65(21):14441-14455. doi: 10.1021/acs.jmedchem.2c00779. Epub 2022 Oct 23.
Addressing glycation-induced oxidative stress in Alzheimer's disease (AD) is an emerging pharmacotherapeutic strategy. Restoration of the brain glyoxalase enzyme system that neutralizes reactive dicarbonyls is one such approach. Toward this end, we designed, synthesized, and evaluated a γ-glutamyl transpeptidase-resistant glyoxalase substrate, ψ-GSH. Although mechanistically successful, the oral efficacy of ψ-GSH appeared as an area in need of improvement. Herein, we describe our rationale for the creation of prodrugs that mask the labile sulfhydryl group. and stability studies identified promising prodrugs that could deliver pharmacologically relevant brain levels of ψ-GSH. When administered orally to a mouse model generated by the intracerebroventricular injection of Aβ1-42, the compounds conferred cognitive benefits. Biochemical and histological examination confirmed their effects on neuroinflammation and oxidative stress. Collectively, we have identified orally efficacious prodrugs of ψ-GSH that are able to restore brain glyoxalase activity and mitigate inflammatory and oxidative pathology associated with AD.
解决阿尔茨海默病（AD）中的糖化诱导氧化应激是一种新兴的治疗策略。恢复中和活性二羰基化合物的脑甘油醛酶酶系统就是这样一种方法。为此，我们设计、合成和评估了一种 γ-谷氨酰转肽酶抗性甘油醛酶底物 ψ-GSH。尽管在机制上取得了成功，但 ψ-GSH 的口服疗效似乎需要改进。在此，我们描述了我们设计掩盖不稳定巯基的前药的原理。并进行了稳定性研究，确定了有前途的前药，这些前药可以提供具有药理相关性的脑水平的 ψ-GSH。当通过脑室内注射 Aβ1-42 向小鼠模型口服给予这些化合物时，它们赋予了认知益处。生化和组织学检查证实了它们对神经炎症和氧化应激的影响。总的来说，我们已经确定了口服有效的 ψ-GSH 前药，能够恢复脑甘油醛酶活性，并减轻与 AD 相关的炎症和氧化病理。
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