Enhancing the Pharmacokinetic Properties of Botulinum Neurotoxin Serotype A Protease Inhibitors through Rational Design
Enhancing the Pharmacokinetic Properties of Botulinum Neurotoxin Serotype A Protease Inhibitors through Rational Design
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DOI：
10.1021/cn200021q
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发表时间：
2011-06-01
影响因子：
5
通讯作者：
Dickerson, Tobin J.
中科院分区：
文献类型：
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作者：
Capek, Petr;Zhang, Yan;Dickerson, Tobin J.
肉毒神经毒素（BoNT）是引起神经麻痹性疾病肉毒中毒的病原体，鉴于这种毒素可能被滥用作为生物恐怖主义的武器，已经成为高度研究的药物靶标。特别地，BoNT血清型A的轻链金属蛋白酶的小分子抑制剂已经受到显著关注，并且已经报道了许多小分子和生物抑制剂。然而，报告的所有小分子都是从初步筛选或药物化学随访研究中鉴定的，这些化合物的药代动力学特征尚未得到解决。在这项研究中，我们已经消除了迄今为止报道的最好的化合物之一2，4-二氯肉桂酸异羟肟酸的药理学责任，并在此过程中发现了一类相关的苯并噻吩异羟肟酸，它们是BoNT/A轻链的显著更有效的抑制剂，同时还具有大大改善的ADME特性，报道了显示BoNT/A轻链最有效抑制的最佳化合物（Ki = 77 nM）。使用将传统药物开发过滤器早期纳入发现过程的策略，BoNT/A先导化合物中的潜在责任已被阐明和消除，为进一步的药理学优化和体内疗效测试扫清了道路。
Botulinum neurotoxin (BoNT), the etiological agent that causes the neuroparalytic disease botulism, has become a highly studied drug target in light of the potential abuse of this toxin as a weapon of bioterrorism. In particular, small molecule inhibitors of the light chain metalloprotease of BoNT serotype A have received significant attention and a number of small molecule and biologic inhibitors have been reported. However, all small molecules reported have been identified from either primary screens or medicinal chemistry follow-up studies, and the pharmacokinetic profiles of these compounds have not been addressed. In this study, we have removed the pharmacologic liabilities of one of the best compounds reported to date, 2,4-dichlorocinnamate hydroxamic acid, and in the process uncovered a related class of benzothiophene hydroxamic acids that are significantly more potent inhibitors of the BoNT/A light chain, while also possessing greatly improved ADME properties, with the best compound showing the most potent inhibition of BoNT/A light chain reported (K-i = 77 nM). Using a strategy of incorporating traditional drug development filters early into the discovery process, potential liabilities in BoNT/A lead compounds have been illuminated and removed, clearing the path for advancement into further pharmacologic optimization and in vivo efficacy testing.