The ‘Ethereal’ nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics
| Autor: | Hélène G. Bazin, Craig L. Johnson, Steven P. Fling, Mark T. Livesay, William S. Bowen, Tim J. Murray, Afsaneh Mozaffarian, Johnson David A, Laura S. Bess, Kendal T. Ryter, Cluff Christopher W, Jeffrey S. Arnold, Jay T. Evans |
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| Rok vydání: | 2008 |
| Předmět: |
Agonist
medicine.drug_class Stereochemistry Chemistry Pharmaceutical Clinical Biochemistry Pharmaceutical Science Ether Models Biological Biochemistry Monocytes Lipid A Inhibitory Concentration 50 Mice chemistry.chemical_compound Glycolipid In vivo Drug Discovery medicine Animals Humans Molecular Biology Glucosamine Tumor Necrosis Factor-alpha Chemistry Organic Chemistry Antagonist Lipids Toll-Like Receptor 4 Ether lipid Models Chemical Drug Design Molecular Medicine lipids (amino acids peptides and proteins) Glycolipids Antagonism |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 18:5350-5354 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2008.09.060 |
| Popis: | To overcome the chemical and metabolic instability of the secondary fatty acyl residues in the AGP class of lipid A mimetics, the secondary ether lipid analogs of the potent TLR4 agonist CRX-527 (2) and TLR4 antagonist CRX-526 (3) were synthesized and evaluated along with their ester counterparts for agonist/antagonist activity in both in vitro and in vivo models. Like CRX-527, the secondary ether lipid 4 showed potent agonist activity in both murine and human models. Ether lipid 5, on the other hand, showed potent TLR4 antagonist activity similar to CRX-526 in human cell assays, but did not display any antagonist activity in murine models and, in fact, was weakly agonistic. Glycolipids 2, 4, and 5 were synthesized via a new highly convergent method utilizing a common advanced intermediate strategy. A new method for preparing (R)-3-alkyloxytetradecanoic acids, a key component of ether lipids 4 and 5, is also described. |
| Databáze: | OpenAIRE |
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