Development of 尾-Amino Alcohol Derivatives That Inhibit Toll-like Receptor 4 Mediated Inflammatory Response as Potential Antiseptics

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• 作者：Sherry A. Chavez ; Alexander J. Martinko ; Corinna Lau ; Michael N. Pham ; Kui Cheng ; Douglas E. Bevan ; Tom E. Mollnes ; Hang Yin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4659-4669
• 全文大小：990K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

Toll-like receptor 4 (TLR4) induced proinflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure鈥揳ctivity relationship and preliminary drug metabolism/pharmacokinetics study of 尾-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with micromolar potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition, the toxicology, specificity, solubility, brain鈥揵lood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis.