Development of β-Amino Alcohol Derivatives That Inhibit Toll-like Receptor 4 Mediated Inflammatory Response as Potential Antiseptics
Year: 2011
Type: article
Abstract: 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.
Source: Journal of Medicinal Chemistry
DOI: 10.1021/jm2003365
Authors: Sherry A. Chavez, Alexander J. Martinko, Corinna Lau, Michael N. Pham, Kui Cheng, Douglas E. Bevan, Tom E. Mollnes, Hang Yin
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1114177658, Transforming Clinical Pain Control by Targeting a Novel Non-Neuronal Receptor, Probing Opioid-Induced Glial Activation with Peptide Antagonists, G3801284106, Optimizing the Clinical Efficacy of Opioids by TLR4 Blockade, G5925976606, G6410635432, Developing Small-Molecule Probes for Opioid-Induced Glial Activation, G7855982944, Colorado Clinical and Translational Science Institute (UL1)
OpenAlex ID: W2088018826