Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309, United States.
J Med Chem. 2011 Jul 14;54(13):4659-69. doi: 10.1021/jm2003365. Epub 2011 Jun 2.
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-activity relationship and preliminary drug metabolism/pharmacokinetics study of β-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-blood 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.
Toll 样受体 4（TLR4）诱导的促炎信号已被直接牵连到严重败血症中，并代表了一个有吸引力的治疗靶点。在此，我们报告了我们对抑制 TLR4 信号通路的β-氨基醇衍生物的结构-活性关系和初步药物代谢/药代动力学研究的调查。从体外细胞实验中鉴定出先导化合物，其对 TLR4 信号的抑制作用具有微摩尔效力，随后在体外全血模型中评估其抑制 TLR4 诱导的炎症反应的能力。此外，还评估了几种化合物的毒理学、特异性、溶解度、血脑屏障通透性和药物代谢情况。尽管还需要进一步优化，但我们的发现为这一类小分子药物的未来开发奠定了基础，可用于治疗严重败血症。
