Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA.
Bioorg Med Chem. 2012 Jan 15;20(2):1029-45. doi: 10.1016/j.bmc.2011.11.039. Epub 2011 Nov 30.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Currently, there is only one FDA-approved treatment for ALS (riluzole), and that drug only extends life, on average, by 2-3 months. Mutations in Cu/Zn superoxide dismutase (SOD1) are found in familial forms of the disease and have played an important role in the study of ALS pathophysiology. On the basis of their activity in a PC12-G93A-YFP high-throughput screening assay, several bioactive compounds have been identified and classified as cyclohexane-1,3-dione (CHD) derivatives. A concise and efficient synthetic route has been developed to provide diverse CHD analogs. The structural modification of the CHD scaffold led to the discovery of a more potent analog (26) with an EC(50) of 700 nM having good pharmacokinetic properties, such as high solubility, low human and mouse metabolic potential, and relatively good plasma stability. It was also found to efficiently penetrate the blood-brain barrier. However, compound 26 did not exhibit any significant life span extension in the ALS mouse model. It was found that, although 26 was active in PC12 cells, it had poor activity in other cell types, including primary cortical neurons, indicating that it can penetrate into the brain, but is not active in neuronal cells, potentially due to poor selective cell penetration. Further structural modification of the CHD scaffold was aimed at improving global cell activity as well as maintaining potency. Two new analogs (71 and 73) were synthesized, which had significantly enhanced cortical neuronal cell permeability, as well as similar potency to that of 26 in the PC12-G93A assay. These CHD analogs are being investigated further as novel therapeutic candidates for ALS.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元的进行性丧失。目前，只有一种获得美国食品药品监督管理局批准用于 ALS 的治疗方法（利鲁唑），而且该药物仅平均延长生命 2-3 个月。铜/锌超氧化物歧化酶（SOD1）的突变存在于疾病的家族形式中，并在 ALS 病理生理学的研究中发挥了重要作用。基于它们在 PC12-G93A-YFP 高通量筛选测定中的活性，已经鉴定出几种具有生物活性的化合物，并将其分类为环己烷-1,3-二酮（CHD）衍生物。已经开发出一种简洁高效的合成途径来提供多种 CHD 类似物。对 CHD 支架的结构修饰导致发现了一种更有效的类似物（26），其 EC50 为 700 nM，具有良好的药代动力学特性，如高溶解度、低人和小鼠代谢潜力以及相对较好的血浆稳定性。它也被发现能够有效地穿透血脑屏障。然而，化合物 26 在 ALS 小鼠模型中并没有表现出任何显著的寿命延长。研究发现，尽管 26 在 PC12 细胞中具有活性，但在其他细胞类型（包括原代皮质神经元）中活性较差，这表明它可以穿透大脑，但在神经元细胞中不活跃，可能是由于选择性细胞穿透能力差。进一步对 CHD 支架进行结构修饰，旨在提高整体细胞活性并保持效力。合成了两种新的类似物（71 和 73），它们显著增强了皮质神经元细胞的通透性，并且在 PC12-G93A 测定中与 26 具有相似的效力。这些 CHD 类似物正在作为 ALS 的新型治疗候选药物进一步研究。
