Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain

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• 作者：Guan-Sheng Jiao^a ; ^&dagger ; ; Seongjin Kim^a ; ^&dagger ; ; Mahtab Moayeri^b ; Devorah Crown^b ; April Thai^a ; Lynne Cregar-Hernandez^a ; Linda McKasson^a ; Banumathi Sankaran^c ; Axel Lehrer^a ; Teri Wong^a ; Lisa Johns^a ; Stephen A. Margosiak^a ; Stephen H. Leppla^b ; Alan T. Johnson^a ; ^{ajohnson@pantherabio.com}
• 关键词：Anthrax ; Lethal factor ; Inhibitor ; In vitro ADME ; X-ray crystallography
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 March, 2012
• 卷：22
• 期：6
• 页码：2242-2246
• 文件大小：460 K

摘要

Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication. Poor efficacy in the rat LT model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. Specific molecular interactions contributing to the high affinity of inhibitors with a secondary amine in the C2-side chain were revealed by X-ray crystallography.