Identification of Clinically Viable Quinolinol Inhibitors of Botulinum Neurotoxin A Light Chain

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• 作者：Dejan Cagli? ; Michelle C. Krutein ; Kristin M. Bompiani ; Deborah J. Barlow ; Galit Benoni ; Jeffrey C. Pelletier ; Allen B. Reitz ; Luke L. Lairson ; Karen L. Houseknecht ; Garry R. Smith ; Tobin J. Dickerson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：669-676
• 全文大小：345K
• ISSN：1520-4804

文摘

Botulinum neurotoxins (BoNT) are the most potent toxins known and a significant bioterrorist threat. Few small molecule compounds have been identified that are active in cell-based or animal models, potentially due to toxin enzyme plasticity. Here we screened commercially available quinolinols, as well as synthesized hydroxyquinolines. Seventy-two compounds had IC₅₀ values below 10 渭M, with the best compound exhibiting submicromolar inhibition (IC₅₀ = 0.8 渭M). Structure鈥揳ctivity relationship trends showed that the enzyme tolerates various substitutions at R₁ but has a clear preference for bulky aryl amide groups at R₂, while methylation at R₃ increased inhibitor potency. Evaluation of the most potent compounds in an ADME panel showed that these compounds possess poor solubility at pH 6.8, but display excellent solubility at low pH, suggesting that oral dosing may be possible. Our data show the potential of quinolinol compounds as BoNT therapeutics due to their good in vitro potencies and favorable ADME properties.