摘要
电压门控钠通道(VGSC)专门负责可兴奋细胞钠离子选择性的涌入.许多生理现象,如肌肉的收缩,疼痛的感觉,大脑中神经元信息的处理,以及周围组织的神经元调节都依赖于这些通道的活性。另一方面,VGSC异常活动有牵连的几个病理过程(如心律失常、癫痫、慢性疼痛),在某些情况下(如离子通道病和myotonias等)常与特定的基因突变相关。事实上,VGSC从未停止吸引药学家的关注,同时对于这些离子通道相关疾病新药物的探索仍在继续。这篇综述中,钠离子通道阻断剂在过去五年报告的审议中,在最有趣的化合物分类基础上,从药物化学的角度来看(i)潜在治疗的应用(ii)靶向VGSC亚型(III)化工材料。最后,通过比较其配体的效率指标,对每个化学型中被选中的具有临床潜力的备选药物进行了评估。对如何改造这些临床前的备选药物的路线进行了讨论。
关键词: 生物物理学;离子通道;化学类型;药物发现;效率指标;电生理;铅化合物;支架。
Current Medicinal Chemistry
Title:Recent Trends in the Discovery of Small Molecule Blockers of Sodium Channels
Volume: 23 Issue: 22
Author(s): Roberta Gualdani, Maria Maddalena Cavalluzzi, Giovanni Lentini
Affiliation:
关键词: 生物物理学;离子通道;化学类型;药物发现;效率指标;电生理;铅化合物;支架。
摘要: Voltage-gated sodium channels (VGSC) are responsible for the selective influx of sodium ions in excitable cells. A number of physiological phenomena such as muscle contraction, pain sensation, processing of neuronal information in the brain as well as neuronal regulation of peripheral tissues rely on the activity of these channels. On the other hand, abnormal activity of VGSC are implicated in several pathological processes (e.g., cardiac arrhythmias, epilepsy, and chronic pain) which in some cases (e.g., channelopathies such as myotonias) are linked to specific gene mutations. As a result, VGSC have never stopped attracting the attention of medicinal chemists and the quest for novel drugs to treat these ion channels-associated diseases continues. In this review, VGSC blocking agents reported in the last lustrum are scrutinised with the aim to give a medicinal chemistry perspective on the most interesting compounds classified on the basis of (i) potential therapeutic application, (ii) targeted VGSC isoforms, and (iii) chemical scaffolds. Finally, the clinical potential of selected drug candidates from each chemotype is evaluated by comparing their ligand efficiency metrics. Possible routes for improvement of these preclinical candidates are also discussed.
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Cite this article as:
Roberta Gualdani, Maria Maddalena Cavalluzzi, Giovanni Lentini , Recent Trends in the Discovery of Small Molecule Blockers of Sodium Channels, Current Medicinal Chemistry 2016; 23 (22) . https://dx.doi.org/10.2174/0929867323666160517121458
DOI https://dx.doi.org/10.2174/0929867323666160517121458 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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