The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics

Bioorg Med Chem Lett. 2008 Oct 15;18(20):5350-4. doi: 10.1016/j.bmcl.2008.09.060. Epub 2008 Sep 19.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Glucosamine / analogs & derivatives
  • Glucosamine / pharmacology
  • Glycolipids / chemistry
  • Humans
  • Inhibitory Concentration 50
  • Lipid A / chemistry*
  • Lipids / chemistry
  • Mice
  • Models, Biological
  • Models, Chemical
  • Monocytes / metabolism
  • Toll-Like Receptor 4 / agonists*
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism


  • CRX-526
  • Glycolipids
  • Lipid A
  • Lipids
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Glucosamine