Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis
Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis
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DOI：
10.1016/j.bmc.2010.10.052
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发表时间：
2011-01-01
影响因子：
3.5
通讯作者：
Silverman, Richard B.
中科院分区：
文献类型：
--
作者：
Chen, Tian;Benmohamed, Radhia;Silverman, Richard B.
肌萎缩性侧索硬化症（ALS）是一种罕见的神经退行性疾病，目前尚无治愈方法。铜/锌超氧化物歧化酶1 （SOD1）的突变与该病的病理生理有关。利用表达突变体G93A SOD1的高通量筛选实验，鉴定了两种生物活性化学命中化合物（1和2），鉴定为芳基磺胺基吡唑酮。该支架的结构优化导致产生更有效的类似物（19），EC50为170 nM。为了确定这类化合物是否适合进一步优化，我进行了一系列药代动力学分析；1的大部分特性对筛选命中都很好，除了它具有相对较快的清除和较短的微粒体半衰期稳定性。化合物2可穿透血脑屏障，脑/血浆比值= 0.19。这类化合物的优化可以为ALS患者提供新的治疗候选药物。(C) 2010 Elsevier Ltd.版权所有。
Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Mutations in copper/zinc superoxide dismutase 1 (SOD1) have been implicated in the pathophysiology of this disease. Using a high-throughput screening assay expressing mutant G93A SOD1, two bioactive chemical hit compounds (1 and 2), identified as arylsulfanyl pyrazolones, were identified. The structural optimization of this scaffold led to the generation of a more potent analogue (19) with an EC50 of 170 nM. To determine the suitability of this class of compounds for further optimization, 1 was subjected to a battery of pharmacokinetic assays; most of the properties of 1 were good for a screening hit, except it had a relatively rapid clearance and short microsomal half-life stability. Compound 2 was found to be blood-brain barrier penetrating with a brain/plasma ratio = 0.19. The optimization of this class of compounds could produce novel therapeutic candidates for ALS patients. (C) 2010 Elsevier Ltd. All rights reserved.