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芳硫基吡唑酮类化合物阻止突变型 SOD1-G93A 聚集。有望用于治疗肌萎缩侧索硬化症。

Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis.

机构信息

Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA.

出版信息

Bioorg Med Chem. 2011 Jan 1;19(1):613-22. doi: 10.1016/j.bmc.2010.10.052. Epub 2010 Oct 30.

Abstract

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 EC(50) of 170nM. 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.

摘要

肌萎缩侧索硬化症(ALS)是一种孤儿神经退行性疾病,目前尚无治愈方法。铜/锌超氧化物歧化酶 1(SOD1)的突变已被牵连到这种疾病的病理生理学中。使用表达突变 G93A SOD1 的高通量筛选测定法,鉴定出两种具有生物活性的化学命中化合物(1 和 2),鉴定为芳基硫基吡唑酮。对该支架进行结构优化,生成了一种效力更高的类似物(19),其 EC50 为 170nM。为了确定此类化合物是否适合进一步优化,1 进行了一系列药代动力学测定;1 的大多数性质都适合筛选命中,除了它具有相对较快的清除率和较短的微粒体半衰期稳定性。发现化合物 2 可穿透血脑屏障,脑/血浆比=0.19。对该类化合物的优化可以为 ALS 患者提供新的治疗候选药物。

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