抗炭疽致死因子中毒的解毒剂。第 3 部分：核心结构的评估和 C2-侧链的进一步修饰。
Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain.
机构信息
PanThera Biopharma, LLC, Aiea, HI 96701, USA.
出版信息
Bioorg Med Chem Lett. 2012 Mar 15;22(6):2242-6. doi: 10.1016/j.bmcl.2012.01.095. Epub 2012 Feb 1.
Abstract
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.
摘要
四种能够提供炭疽致死因子（LF）纳摩尔级以下抑制剂的核心结构，通过比较毒性、物理化学性质、体外 ADME 特征以及在 LF 中毒的大鼠致死毒素（LT）模型中的相对疗效进行了评估。苯氧乙酸系列（3）在大鼠 LT 模型中表现出的低疗效与大鼠微粒体和血浆稳定性差有关。通过 X 射线晶体学揭示了导致具有 C2-侧链仲胺的抑制剂具有高亲和力的特定分子相互作用。
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