Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 13, Pages 4659-4669Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm2003365
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Funding
- National Institutes of Health [DA026950, DA025740, NS067425, RR025780, DA029119]
- China Scholarship Council [2009619072]
- CU Undergraduate Research Opportunities Program
- HHMI Biosciences
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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 beta-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.
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